Variant nucleic acid libraries for coronavirus

ABSTRACT

Provided herein are methods and compositions relating to libraries of optimized antibodies having nucleic acids encoding for an antibody comprising modified sequences. Libraries described herein comprise nucleic acids encoding SARS-CoV-2 or ACE2 antibodies. Further described herein are protein libraries generated when the nucleic acid libraries are translated. Further described herein are cell libraries expressing variegated nucleic acid libraries described herein.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Patent Application No. 63/115,568 filed on Nov. 18, 2020, U.S. Provisional Patent Application No. 63/104,465 filed on Oct. 22, 2020, U.S. Provisional Patent Application No. 63/073,362 filed on Sep. 1, 2020, U.S. Provisional Patent Application No. 63/069,665 filed on Aug. 24, 2020, U.S. Provisional Patent Application No. 63/034,896 filed on Jun. 4, 2020, U.S. Provisional Patent Application No. 63/016,254 filed on Apr. 27, 2020, each of which is incorporated by reference in its entirety.

BACKGROUND

Coronaviruses like severe acute respiratory coronavirus 2 (SARS-CoV-2) can cause severe respiratory problems. Therapies are needed for treating and preventing viral infection caused by coronaviruses like SARS-CoV-2. Antibodies possess the capability to bind with high specificity and affinity to biological targets. However, the design of therapeutic antibodies is challenging due to balancing of immunological effects with efficacy. Thus, there is a need to develop compositions and methods for the optimization of antibody properties in order to develop effective therapies for treating coronavirus infections.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF SUMMARY

Provided herein are nucleic acid libraries comprising: a plurality of sequences that when translated encode for antibodies or antibody fragments that bind to SARS-CoV-2 or ACE2 protein, wherein each of the sequences comprises a predetermined number of variants within a CDR relative to an input sequence that encodes an antibody, and wherein the library comprises at least 50,000 variant sequences. Further provided herein are nucleic acid libraries, wherein the antibodies or antibody fragments bind to a spike glycoprotein, a membrane protein, an envelope protein, a nucleocapsid protein, or combinations thereof of the SARS-CoV-2. Further provided herein are nucleic acid libraries, wherein the antibodies or antibody fragments bind to a spike glycoprotein. Further provided herein are nucleic acid libraries, wherein the antibodies or antibody fragment bind to a receptor binding domain of the spike glycoprotein. Further provided herein are nucleic acid libraries, wherein the library comprises at least 100,000 variant sequences. Further provided herein are nucleic acid libraries, wherein at least some of the sequences encode for an antibody light chain. Further provided herein are nucleic acid libraries, wherein at least some of the sequences encode for an antibody heavy chain. Further provided herein are nucleic acid libraries, wherein each sequence of the plurality of sequences comprises at least one variant in the CDR of a heavy chain or light chain relative to the input sequence. Further provided herein are nucleic acid libraries, wherein each sequence of the plurality of sequences comprises at least two variants in the CDR of a heavy chain or light chain relative to the input sequence. Further provided herein are nucleic acid libraries, wherein at least one of the variants is present in at least two individuals. Further provided herein are nucleic acid libraries, wherein at least one of the variants is present in at least three individuals. Further provided herein are nucleic acid libraries, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 5× higher binding affinity than a binding affinity of the input sequence. Further provided herein are nucleic acid libraries, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 25× higher binding affinity than a binding affinity of the input sequence. Further provided herein are nucleic acid libraries, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 50× higher binding affinity than a binding affinity of the input sequence. Further provided herein are nucleic acid libraries, wherein each sequence of the plurality of sequences comprises at least one variant in the CDR of a heavy chain or light chain relative to a germline sequence of the input sequence. Further provided herein are nucleic acid libraries, wherein the CDR is a CDR1, CDR2, and CDR3 on a heavy chain. Further provided herein are nucleic acid libraries, wherein the CDR is a CDR1, CDR2, and CDR3 on a light chain. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having at least 70× higher binding affinity than the input sequence. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having a K_(D) of less than 50 nM. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having a K_(D) of less than 25 nM. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having a K_(D) of less than 10 nM. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having a K_(D) of less than 5 nM. Further provided herein are nucleic acid libraries, wherein the library encodes a CDR sequence of any one of SEQ ID NOs: 1-921, 1047-1208, 1263-1436, 1495-1917, or 2059-2598.

Provided herein are nucleic acid libraries comprising: a plurality of sequences that when translated encode for antibodies or antibody fragments that bind to a coronavirus or a receptor of the coronavirus, wherein each of the sequences comprises a predetermined number of variants within a CDR relative to an input sequence that encodes an antibody, and wherein the library comprises at least 50,000 variant sequences. Further provided herein are nucleic acid libraries, wherein the coronavirus is SARS-CoV, MERS-CoV, CoV-229E, HCoV-NL63, HCoV-OC43, or HCoV-HKU1. Further provided herein are nucleic acid libraries, wherein the receptor of the coronavirus is ACE2 or dipeptidyl peptidase 4 (DPP4). Further provided herein are nucleic acid libraries, wherein the library comprises at least 100,000 variant sequences. Further provided herein are nucleic acid libraries, wherein at least some of the sequences encode for an antibody light chain. Further provided herein are nucleic acid libraries, wherein at least some of the sequences encode for an antibody heavy chain. Further provided herein are nucleic acid libraries, wherein each sequence of the plurality of sequences comprises at least one variant in the CDR of a heavy chain or light chain relative to the input sequence. Further provided herein are nucleic acid libraries, wherein each sequence of the plurality of sequences comprises at least two variants in the CDR of a heavy chain or light chain relative to the input sequence. Further provided herein are nucleic acid libraries, wherein at least one of the variants is present in at least two individuals. Further provided herein are nucleic acid libraries, wherein at least one of the variants is present in at least three individuals. Further provided herein are nucleic acid libraries, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 5× higher binding affinity than a binding affinity of the input sequence. Further provided herein are nucleic acid libraries, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 25× higher binding affinity than a binding affinity of the input sequence. Further provided herein are nucleic acid libraries, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 50× higher binding affinity than a binding affinity of the input sequence. Further provided herein are nucleic acid libraries, wherein each sequence of the plurality of sequences comprises at least one variant in the CDR of a heavy chain or light chain relative to a germline sequence of the input sequence. Further provided herein are nucleic acid libraries, wherein the CDR is a CDR1, CDR2, and CDR3 on a heavy chain. Further provided herein are nucleic acid libraries, wherein the CDR is a CDR1, CDR2, and CDR3 on a light chain. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having at least 70× higher binding affinity than the input sequence. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having a K_(D) of less than 50 nM. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having a K_(D) of less than 25 nM. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having a K_(D) of less than 10 nM. Further provided herein are nucleic acid libraries, wherein the at least one sequence that when translated encodes for an antibody or antibody fragment having a K_(D) of less than 5 nM.

Provided herein are antibodies, wherein the antibody comprises a sequence comprising at least 90% sequence identity to any one of SEQ ID NOs: 1-2668.

Provided herein are antibodies, wherein the antibody comprises a sequence comprising at least 90% sequence identity to SEQ ID NOs: 1-2668; and wherein the antibody is a monoclonal antibody, a polyclonal antibody, a bi-specific antibody, a multispecific antibody, a grafted antibody, a human antibody, a humanized antibody, a synthetic antibody, a chimeric antibody, a camelized antibody, a single-chain Fvs (scFv), a single chain antibody, a Fab fragment, a F(ab′)2 fragment, a Fd fragment, a Fv fragment, a single-domain antibody, an isolated complementarity determining region (CDR), a diabody, a fragment comprised of only a single monomeric variable domain, disulfide-linked Fvs (sdFv), an intrabody, an anti-idiotypic (anti-Id) antibody, or ab antigen-binding fragments thereof.

Provided herein are methods of treating a SARS-CoV-2 infection, comprising administering the antibody as described herein. Further provided herein are methods, wherein the antibody is administered prior to exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at least about 1 week prior to exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at least about 1 month prior to exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at least about 5 months prior to exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered after exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at most about 24 hours after exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at most about 1 week after exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at most about 1 month after exposure to SARS-CoV-2.

Provided herein are methods of treating an individual with a SARS-CoV-2 infection with the antibody as described herein comprising: (a) obtaining or having obtained a sample from the individual; (b) performing or having performed an expression level assay on the sample to determine expression levels of SARS-CoV-2 antibodies; and (c) if the sample has an expression level of the SARS-CoV-2 antibodies then administering to the individual the antibody as described herein, thereby treating the SARS-CoV-2 infection.

Provided herein are methods for optimizing an antibody comprising: (a) providing a plurality of polynucleotide sequences encoding for an antibody or antibody fragment, wherein the antibody or antibody fragment is derived from a subject having SARS-CoV-2; (b) generating a nucleic acid library comprising the plurality of sequences that when translated encode for antibodies or antibody fragments that bind SARS-CoV-2 or ACE2 protein, wherein each of the sequences comprises a predetermined number of variants within a CDR relative to an input sequence that encodes an antibody; wherein the library comprises at least 50,000 variant sequences; and (c) synthesizing the at least 50,000 variant sequences. Further provided herein are methods, wherein the antibody library comprises at least 100,000 sequences. Further provided herein are methods, wherein the method further comprises enriching a subset of the variant sequences. Further provided herein are methods, wherein the method further comprises expressing the antibody or antibody fragments corresponding to the variant sequences. Further provided herein are methods, wherein the polynucleotide sequence is a murine, human, or chimeric antibody sequence. Further provided herein are methods, wherein each sequence of the plurality of variant sequences comprises at least one variant in each CDR of a heavy chain or light chain, relative to the input sequence. Further provided herein are methods, wherein each sequence of the plurality of variant sequences comprises at least two variants in each CDR of a heavy chain or light chain relative to the input sequence. Further provided herein are methods, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 5× higher binding affinity than a binding affinity of the input sequence. Further provided herein are methods, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 25× higher binding affinity than a binding affinity of the input sequence. Further provided herein are methods, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 50× higher binding affinity than a binding affinity of the input sequence. Further provided herein are methods, wherein each sequence comprises at least one variant in each CDR of a heavy chain or light chain relative to a germline sequence of the input sequence. Further provided herein are methods, wherein the nucleic acid library has a theoretical diversity of at least 10¹⁰ sequences. Further provided herein are methods, wherein the nucleic acid library has a theoretical diversity of at least 10¹² sequences.

Provided herein are antibodies or antibody fragments comprising a variable domain, heavy chain region (VH) and a variable domain, light chain region (VL), wherein VH comprises complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein VL comprises complementarity determining regions CDRL1, CDRL2, and CDRL3, and wherein (a) an amino acid sequence of CDRH1 is as set forth in any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575; (b) an amino acid sequence of CDRH2 is as set forth in any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604; (c) an amino acid sequence of CDRH3 is as set forth in any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633; (d) an amino acid sequence of CDRL1 is as set forth in any one of SEQ ID NOs: 196-210, 286-300, 412-438, and 634-662; (e) an amino acid sequence of CDRL2 is as set forth in any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691; and (f) an amino acid sequence of CDRL3 is as set forth in any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720. Further provided herein are antibodies or antibody fragments, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 155; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 170; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 185; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 200; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 215; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 230. Further provided herein are antibodies or antibody fragments, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 152; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 167; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 182; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 197; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 212; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 227. Further provided herein are antibodies or antibody fragments, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 335; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 362; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 389; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 199; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 214; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 229. Further provided herein are antibodies or antibody fragments, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 336; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 363; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 390; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 201; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 216; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 231. Further provided herein are antibodies or antibody fragments, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 158; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 173; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 188; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 203; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 218; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 233. Further provided herein are antibodies or antibody fragments, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 551; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 580; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 609; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 290; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 305; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 320. Further provided herein are antibodies or antibody fragments, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 549; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 578; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 607; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 292; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 307; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 322. Further provided herein are antibodies or antibody fragments, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 552; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 581; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 610; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 291; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 306; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 321. Further provided herein are antibodies or antibody fragments, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 554; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 583; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 612; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 288; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 303; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 318. Further provided herein are antibodies or antibody fragments, wherein the antibody or antibody fragment binds to a spike glycoprotein. Further provided herein are antibodies or antibody fragments, wherein the antibody or antibody fragment binds to a receptor binding domain of the spike glycoprotein. Further provided herein are antibodies or antibody fragments, wherein the antibody or antibody fragment comprises a K_(D) of less than 50 nM. Further provided herein are antibodies or antibody fragments, wherein the antibody or antibody fragment comprises a K_(D) of less than 25 nM. Further provided herein are antibodies or antibody fragments, wherein the antibody or antibody fragment comprises a K_(D) of less than 10 nM. Further provided herein are antibodies or antibody fragments, wherein the antibody or antibody fragment comprises a K_(D) of less than 5 nM.

Provided herein are antibodies or antibody fragments comprising a variable domain, heavy chain region (VH) wherein VH comprises complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein (a) an amino acid sequence of CDRH1 is as set forth in any one of SEQ ID NOs: 1-50, 779-919, 1344-1523, and 2381-2452; (b) an amino acid sequence of CDRH2 is as set forth in any one of SEQ ID NOs: 51-100, 920-1061, 1524-1703, and 2453-2524; and (c) an amino acid sequence of CDRH3 is as set forth in any one of SEQ ID NOs: 101-150, 1062-1202, 1704-1883, and 2525-2596. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 1414; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 1594; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1774. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 1447; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 1627; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1807. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 1474; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 1654; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1834. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 1344; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 1524; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1704. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 1363; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 1543; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1723. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 1487; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 1667; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1847. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 780; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 921; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1063. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 782; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 923; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1065. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 39; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 89; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 139. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 832; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 973; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1115. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 869; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 1010; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1152. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 889; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 1030; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1172. Further provided herein are antibodies or antibody fragments, wherein (a) the amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 908; (b) the amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 1049; and (c) the amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 1191.

Provided herein are antibodies or antibody fragments comprising a variable domain, heavy chain region (VH) and a variable domain, light chain region (VL), wherein the VH comprises an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 493-519 and 721-749, and wherein the VL comprises an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 520-546 and 750-778.

Provided herein are antibodies or antibody fragments comprising a variable domain, heavy chain region (VH) comprising an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 1884-2063, 2302-2380, and 2597-2668. Further provided herein are antibodies or antibody fragments, wherein the VH comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 1954. Further provided herein are antibodies or antibody fragments, wherein the VH comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 1987. Further provided herein are antibodies or antibody fragments, wherein the VH comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 2014.

Provided herein are antibodies, wherein the antibody comprises a sequence comprising at least 90% sequence identity to any one of SEQ ID NOs: 1-2668; and wherein the antibody is a monoclonal antibody, a polyclonal antibody, a bi-specific antibody, a multispecific antibody, a grafted antibody, a human antibody, a humanized antibody, a synthetic antibody, a chimeric antibody, a camelized antibody, a single-chain Fvs (scFv), a single chain antibody, a Fab fragment, a F(ab′)2 fragment, a Fd fragment, a Fv fragment, a single-domain antibody, an isolated complementarity determining region (CDR), a diabody, a fragment comprised of only a single monomeric variable domain, disulfide-linked Fvs (sdFv), an intrabody, an anti-idiotypic (anti-Id) antibody, or ab antigen-binding fragments thereof.

Provided herein are nucleic acid compositions comprising: a) a first nucleic acid encoding a variable domain, heavy chain region (VH) comprising an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 493-519 and 721-749; b) a second nucleic acid encoding a variable domain, light chain region (VL) comprising at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 520-546 and 750-778; and an excipient.

Provided herein are nucleic acid compositions comprising: a) a first nucleic acid encoding a variable domain, heavy chain region (VH) comprising an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 1884-2063, 2302-2380, and 2597-2668; and b) an excipient. Further provided herein are nucleic acid compositions, wherein the VH comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 1954. Further provided herein are nucleic acid compositions, wherein the VH comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 1987. Further provided herein are nucleic acid compositions, wherein the VH comprises an amino acid sequence at least about 90% identical to SEQ ID NO: 2014.

Provided herein are methods of treating a SARS-CoV-2 infection, comprising administering the antibody or antibody fragment described herein. Further provided herein are methods, wherein the antibody is administered prior to exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at least about 1 week prior to exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at least about 1 month prior to exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at least about 5 months prior to exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered after exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at most about 24 hours after exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at most about 1 week after exposure to SARS-CoV-2. Further provided herein are methods, wherein the antibody is administered at most about 1 month after exposure to SARS-CoV-2. Further provided herein are methods of treating an individual with a SARS-CoV-2 infection with the antibody or antibody fragment described herein comprising: a) obtaining or having obtained a sample from the individual; b) performing or having performed an expression level assay on the sample to determine expression levels of SARS-CoV-2 antibodies; and if the sample has an expression level of the SARS-CoV-2 antibodies then administering to the individual the antibody or antibody fragment described herein, thereby treating the SARS-CoV-2 infection. Further provided herein are methods for optimizing an antibody comprising: a) providing a plurality of polynucleotide sequences encoding for an antibody or antibody fragment, wherein the antibody or antibody fragment is derived from a subject having SARS-CoV-2; b) generating a nucleic acid library comprising the plurality of sequences that when translated encode for antibodies or antibody fragments that bind SARS-CoV-2 or ACE2 protein, wherein each of the sequences comprises a predetermined number of variants within a CDR relative to an input sequence that encodes an antibody; wherein the library comprises at least 50,000 variant sequences; and c) synthesizing the at least 50,000 variant sequences. Further provided herein are methods, wherein the antibody library comprises at least 100,000 sequences. Further provided herein are methods, wherein the method further comprises enriching a subset of the variant sequences. Further provided herein are methods, wherein the method further comprises expressing the antibody or antibody fragments corresponding to the variant sequences. Further provided herein are methods, wherein the polynucleotide sequence is a murine, human, or chimeric antibody sequence. Further provided herein are methods, wherein each sequence of the plurality of variant sequences comprises at least one variant in each CDR of a heavy chain or light chain, relative to the input sequence. Further provided herein are methods, wherein each sequence of the plurality of variant sequences comprises at least two variants in each CDR of a heavy chain or light chain relative to the input sequence. Further provided herein are methods, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 5× higher binding affinity than a binding affinity of the input sequence. Further provided herein are methods, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 25× higher binding affinity than a binding affinity of the input sequence. Further provided herein are methods, wherein at least one sequence when translated encodes for an antibody or antibody fragment having at least 50× higher binding affinity than a binding affinity of the input sequence. Further provided herein are methods, wherein each sequence comprises at least one variant in each CDR of a heavy chain or light chain relative to a germline sequence of the input sequence. Further provided herein are methods, wherein the nucleic acid library has a theoretical diversity of at least 10¹⁰ sequences. Further provided herein are methods, wherein the nucleic acid library has a theoretical diversity of at least 10¹² sequences.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a workflow for antibody optimization.

FIG. 2 presents a diagram of steps demonstrating an exemplary process workflow for gene synthesis as disclosed herein.

FIG. 3 illustrates an example of a computer system.

FIG. 4 is a block diagram illustrating an architecture of a computer system.

FIG. 5 is a diagram demonstrating a network configured to incorporate a plurality of computer systems, a plurality of cell phones and personal data assistants, and Network Attached Storage (NAS).

FIG. 6 is a block diagram of a multiprocessor computer system using a shared virtual address memory space.

FIG. 7 is a schema of a panning workflow.

FIGS. 8A-8B are graphs of panning data from round 4 for antibody 1.

FIGS. 8C-8D are graphs of panning data from round 4 for antibody 2.

FIGS. 9A-9B are graphs of panning data from round 4 for antibody 3.

FIGS. 9C-9D are graphs of panning data from round 4 for antibody 4.

FIG. 10 shows graphs of ACE2 binding to SARS-CoV-2 variant antibodies.

FIGS. 11A-11B are graphs of affinity data for SARS-CoV-2 variant antibodies.

FIGS. 12A-12C are graphs of affinity data for ACE2 variant antibodies.

FIG. 13 is a graph of binding of SARS-CoV-2 variant antibodies to S1 protein.

FIG. 14 is a graph of variant 4-23 binding in VERO E6 cells.

FIGS. 15A-15C are graphs of variant antibody binding in VERO E6 cells.

FIG. 15D is a graph of data from S1 RBD ACE2 inhibitor ELISA.

FIG. 16A-16B are graphs of SARS-CoV-2 and ACE2 competition ELISAs.

FIG. 17A is a graph of SARS-CoV-2 and ACE2 competition ELISAs from a first set.

FIG. 17B is a graph of SARS-CoV-2 and ACE2 competition ELISAs from a first set showing SARS-CoV-2 variant antibodies.

FIGS. 18A-18B are graphs from a first set (FIG. 18A) and second set (FIG. 18B) showing ACE2 variant antibodies.

FIGS. 18C-18D are graphs of SARS-CoV-2 variant antibodies in neutralization assays.

FIG. 19 is a graph of anti-ACE2 inhibitors.

FIG. 20 is a graph of SARS-CoV-2 and ACE2 inhibition.

FIGS. 21A-21D are graphs of SARS-CoV-2 variant antibodies on VERO E6 inhibition measured by FACS.

FIGS. 22A-22B are graphs of SARS-CoV-2 variant antibodies on VERO E6 inhibition measured by FACS as compared to CR3022.

FIGS. 22C-22D are graphs of affinity of SARS-CoV-2 variant antibodies determined by coating ELISA plates with SARS-CoV-2 Spike Glycoprotein S1 (FIG. 22C) or S protein trimer (FIG. 22D).

FIG. 22E is a graph of mean fluorescent intensity (MFI) plotted for each SARS-CoV-2 variant antibody dilution.

FIG. 23 are images from bluDiagnostics assay of CR3022 and variant 2-6.

FIGS. 24A-24B are graphs of phage ELISA data from panning data for antibody 5 (FIG. 24A) and antibody 6 (FIG. 24B).

FIGS. 25A-251I are graphs of phage ELISA for antibody 5 variants.

FIGS. 26A-26J are graphs of phage ELISA for antibody 6 variants.

FIGS. 27A-27B are graphs of phage ELISA for select antibody 6 variants.

FIGS. 28A-28F are graphs of phage ELISA for antibody 5 variants using 1 nM and 0.1 nM concentrations of antibodies.

FIGS. 29A-29J are graphs of phage ELISA for antibody 6 variants using 1 nM and 0.1 nM concentrations of antibodies.

FIGS. 30A-30C are graphs of mean fluorescent intensity (MFI) plotted for each SARS-CoV-2 variant antibody dilution.

FIGS. 31A-31B are graphs of antibody kinetics for variants 2-5, 2-2, and 2-6 (FIG. 31A) and variants 1-12, 1-42, 1-20, and 1-19 (FIG. 31B).

FIG. 31C is a graph of percent neutralization for variants 1-12, 1-42 and 1-20.

FIG. 31D is a graph of percent neutralization for variants 1-12, 1-42 and 1-20 using live virus.

FIG. 32 is a graph of ACE Activity in the presence of variant ACE2 antibodies.

FIGS. 33A-33D are graphs of variant antibodies neutralizing live virus.

FIG. 33E is a graph of variant antibodies neutralizing live virus FRNT.

FIG. 33F-33I show data of variant antibodies neutralizing live virus PRNT.

FIG. 34A shows a graph of percent weight change (y-axis) versus day post injection (PI, x-axis) for positive control convalescent plasma and negative control Mab c7d11.

FIG. 34B shows a graph of percent weight change (y-axis) versus day post injection (PI, x-axis) for variant antibody 6-63.

FIG. 34C shows a graph of percent weight change (y-axis) versus day post injection (PI, x-axis) for variant antibody 6-3.

FIG. 34D shows a graph of percent weight change (y-axis) versus day post injection (PI, x-axis) for variant antibody 6-36.

FIG. 34E shows graphs of percent weight change (y-axis) versus day post injection (PI, x-axis) based on dose.

FIG. 34F shows graphs of percent weight change (y-axis) versus day post injection (PI, x-axis) based on dose for variant antibodies 2-3, 2-63, and 1-20.

FIG. 34G shows a graph of data from a plaque assay to detect infectious virus in Day 9 lungs. The indicated antibodies were administered Day −1. Lungs were collected on Day 9, the right lobe was homogenized, clarified and supernatants were quantified by plaque titration. Individual hamster values are shown as symbols. White symbols indicate no infectious virus detected. The geometric mean PFU/gram is shown as bars. Limit of assay shown as dotted line.

FIG. 34H shows a graph of data from in situ hybridization (ISH) to detect infected cells in Day 9 lungs. The indicated antibodies were administered Day −1. Three animals per group were analyzed. Individual hamster values are shown as symbols. Median ISH scores are shown as bars.

FIG. 34I shows a graph of data from cumulative inflammation and edema scores for Day 9 lungs. The indicated antibodies were administered Day −1. Three animals per group were analyzed. Individual hamster cumulative pathology scores are shown as symbols. Median scores are shown as bars.

FIG. 35 shows an exemplary sequence of a SARS-CoV-2 membrane glycoprotein construct.

FIGS. 36A-36D show graphs of membrane glycoprotein variant antibodies binding.

FIG. 37A-37B show graphs of ELISA assays of membrane glycoprotein variant antibodies.

FIGS. 38A-38J show graphs of FACS titration data for membrane glycoprotein variant antibodies.

FIGS. 39A-39B show graphs of binding affinity and binding for membrane glycoprotein variant antibodies.

FIGS. 40A-40D show graphs of flow titrations for pool and single pool HEK for membrane protein antibodies.

FIG. 41A shows a graph of the positive control pAb in a neutralization assay.

FIG. 41B shows a graph of neutralization of antibodies 6-63, 6-3, and 1-12 in VSV-SARS B.135 strain.

FIG. 42A shows a graph of the positive control in a neutralization assay.

FIGS. 42B-42C show graphs of neutralization by antibodies described herein.

FIG. 43A shows graphs weight change. Animals were immunosuppressed and then exposed to SARS-CoV-2 virus, WA1 strain, on Day 0. Top graph indicates data from the control group that received the cocktail on Day −1 (D-1, Group A). A group was immunosuppressed but not exposed to virus (CYP Control, Group I). Negative control is an IgG monoclonal (Group H). The cocktail was administered on the indicated day post-exposure (Groups B-G; middle and bottom graphs). Arrows indicate day of antibody administration. Symbols are mean±SEM. Statistical differences in the area under the curve (AOC) are shown to the right of each line. * indicates p value <0.05, ns=not significant.

FIG. 43B shows a graph of data from FIG. 43A plotted on one graph.

FIG. 43C shows a graph of infectious virus in lungs on Day 14. Plaque assays were run on Day 14 lung homogenates. Plaque forming units (PFU) per gram of tissue were calculated and plotted. The limit of the assay is shown as a dotted line. Bars are the geometric means for each group. Group ID are in parentheses. White symbols indicated no infectious virus was detected. CYP=cyclophosphamide; Neg=Negative; Cont=control.

FIG. 43D shows a graph infectious virus in lungs of untreated control hamsters. CYP-treated animals were exposed to 1,000 pfu of virus by intranasal route on Day 0. Groups of four animals were euthanized and lungs were collected on the indicated days. Lung homogenates were assayed for infectious virus by plaque assay. Plaque forming units (PFU) per gram lung tissue are plotted. Geometric mean titers and SD are shown.

DETAILED DESCRIPTION

The present disclosure employs, unless otherwise indicated, conventional molecular biology techniques, which are within the skill of the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art.

Definitions

Throughout this disclosure, various embodiments are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of any embodiments. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range to the tenth of the unit of the lower limit unless the context clearly dictates otherwise. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual values within that range, for example, 1.1, 2, 2.3, 5, and 5.9. This applies regardless of the breadth of the range. The upper and lower limits of these intervening ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, unless the context clearly dictates otherwise.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of any embodiment. As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items.

Unless specifically stated or obvious from context, as used herein, the term “about” in reference to a number or range of numbers is understood to mean the stated number and numbers+/−10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.

Unless specifically stated, as used herein, the term “nucleic acid” encompasses double- or triple-stranded nucleic acids, as well as single-stranded molecules. In double- or triple-stranded nucleic acids, the nucleic acid strands need not be coextensive (i.e., a double-stranded nucleic acid need not be double-stranded along the entire length of both strands). Nucleic acid sequences, when provided, are listed in the 5′ to 3′ direction, unless stated otherwise. Methods described herein provide for the generation of isolated nucleic acids. Methods described herein additionally provide for the generation of isolated and purified nucleic acids. A “nucleic acid” as referred to herein can comprise at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or more bases in length. Moreover, provided herein are methods for the synthesis of any number of polypeptide-segments encoding nucleotide sequences, including sequences encoding non-ribosomal peptides (NRPs), sequences encoding non-ribosomal peptide-synthetase (NRPS) modules and synthetic variants, polypeptide segments of other modular proteins, such as antibodies, polypeptide segments from other protein families, including non-coding DNA or RNA, such as regulatory sequences e.g. promoters, transcription factors, enhancers, siRNA, shRNA, RNAi, miRNA, small nucleolar RNA derived from microRNA, or any functional or structural DNA or RNA unit of interest. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, intergenic DNA, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), small nucleolar RNA, ribozymes, complementary DNA (cDNA), which is a DNA representation of mRNA, usually obtained by reverse transcription of messenger RNA (mRNA) or by amplification; DNA molecules produced synthetically or by amplification, genomic DNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. cDNA encoding for a gene or gene fragment referred herein may comprise at least one region encoding for exon sequences without an intervening intron sequence in the genomic equivalent sequence. cDNA described herein may be generated by de novo synthesis.

Antibody Optimization Library for Coronavirus

Provided herein are methods, compositions, and systems for the optimization of antibodies for coronavirus. In some embodiments, the antibodies are optimized for SARS-CoV, MERS-CoV, CoV-229E, HCoV-NL63, HCoV-OC43, or HCoV-HKU1. In some embodiments, the antibodies are optimized for SARS-CoV-2. In some embodiments, the antibodies are optimized for a receptor that binds to the coronavirus. In some embodiments, the receptor of the coronavirus is ACE2 or dipeptidyl peptidase 4 (DPP4). In some embodiments, the antibodies are optimized based on interactions between the coronavirus and the receptor that binds the coronavirus. In some embodiments, the antibodies are optimized for angiotensin-converting enzyme 2 (ACE2). In some embodiments, the antibodies are optimized based on interactions between SARS-CoV-2 and ACE2.

Antibodies are in some instances optimized by the design of in-silico libraries comprising variant sequences of an input antibody sequence (FIG. 1). Input sequences 100 are in some instances modified in-silico 102 with one or more mutations or variants to generate libraries of optimized sequences 103. In some instances, such libraries are synthesized, cloned into expression vectors, and translation products (antibodies) evaluated for activity. In some instances, fragments of sequences are synthesized and subsequently assembled. In some instances, expression vectors are used to display and enrich desired antibodies, such as phage display. Selection pressures used during enrichment in some instances includes, but is not limited to, binding affinity, toxicity, immunological tolerance, stability, receptor-ligand competition, or developability. Such expression vectors allow antibodies with specific properties to be selected (“panning”), and subsequent propagation or amplification of such sequences enriches the library with these sequences Panning rounds can be repeated any number of times, such as 1, 2, 3, 4, 5, 6, 7, or more than 7 rounds. Sequencing at one or more rounds is in some instances used to identify which sequences 105 have been enriched in the library.

Described herein are methods and systems of in-silico library design. For example, an antibody or antibody fragment sequence is used as input. In some instances, the antibody sequence used as input is an antibody or antibody fragment sequence that binds SARS-CoV-2. In some instances, the input is an antibody or antibody fragment sequence that binds a protein of SARS-CoV-2. In some instances, the protein is a spike glycoprotein, a membrane protein, an envelope protein, a nucleocapsid protein, or combinations thereof. In some instances, the protein is a spike glycoprotein of SARS-CoV-2. In some instances, the protein is a receptor binding domain of SARS-CoV-2. In some instances, the input sequence is an antibody or antibody fragment sequence that binds angiotensin-converting enzyme 2 (ACE2). In some instances, the input sequence is an antibody or antibody fragment sequence that binds an extracellular domain of the angiotensin-converting enzyme 2 (ACE2).

A database 102 comprising known mutations or variants of one or more viruses is queried 101, and a library 103 of sequences comprising combinations of these mutations or variants are generated. In some instances, the database comprises known mutations or variants of SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or combinations thereof. In some instances, the database comprises known mutations or variants of the spike protein of SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or combinations thereof. In some instances, the database comprises known mutations or variants of the receptor binding domain of SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or combinations thereof. In some instances, the database comprises mutations or variants of a protein of SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or combinations thereof that binds to ACE2.

In some instances, the input sequence is a heavy chain sequence of an antibody or antibody fragment that binds SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or combinations thereof. In some instances, the input sequence is a light chain sequence of an antibody or antibody fragment that binds SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or combinations thereof. In some instances, the heavy chain sequence comprises varied CDR regions. In some instances, the light chain sequence comprises varied CDR regions. In some instances, known mutations or variants from CDRs are used to build the sequence library. Filters 104, or exclusion criteria, are in some instances used to select specific types of variants for members of the sequence library. For example, sequences having a mutation or variant are added if a minimum number of organisms in the database have the mutation or variant. In some instances, additional CDRs are specified for inclusion in the database. In some instances, specific mutations or variants or combinations of mutations or variants are excluded from the library (e.g., known immunogenic sites, structure sites, etc.). In some instances, specific sites in the input sequence are systematically replaced with histidine, aspartic acid, glutamic acid, or combinations thereof. In some instances, the maximum or minimum number of mutations or variants allowed for each region of an antibody are specified. Mutations or variants in some instances are described relative to the input sequence or the input sequence's corresponding germline sequence. For example, sequences generated by the optimization comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more than 16 mutations or variants from the input sequence. In some instances, sequences generated by the optimization comprise no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or no more than 18 mutations or variants from the input sequence. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or about 18 mutations or variants relative to the input sequence. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input sequence in a first CDR region. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input sequence in a second CDR region. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input sequence in a third CDR region. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input sequence in a first CDR region of a heavy chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input sequence in a second CDR region of a heavy chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input sequence in a third CDR region of a heavy chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input sequence in a first CDR region of a light chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input sequence in a second CDR region of a light chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input sequence in a third CDR region of a light chain. In some instances, a first CDR region is CDR1. In some instances, a second CDR region is CDR2. In some instances, a third CDR region is CDR3. In-silico antibodies libraries are in some instances synthesized, assembled, and enriched for desired sequences.

The germline sequences corresponding to an input sequence may also be modified to generate sequences in a library. For example, sequences generated by the optimization methods described herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more than 16 mutations or variants from the germline sequence. In some instances, sequences generated by the optimization comprise no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or no more than 18 mutations or variants from the germline sequence. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or about 18 mutations or variants relative to the germline sequence.

Provided herein are methods, systems, and compositions for antibody optimization, wherein the input sequence comprises mutations or variants in an antibody region. Exemplary regions of the antibody include, but are not limited to, a complementarity-determining region (CDR), a variable domain, or a constant domain. In some instances, the CDR is CDR1, CDR2, or CDR3. In some instances, the CDR is a heavy domain including, but not limited to, CDRH1, CDRH2, and CDRH3. In some instances, the CDR is a light domain including, but not limited to, CDRL1, CDRL2, and CDRL3. In some instances, the variable domain is variable domain, light chain (VL) or variable domain, heavy chain (VH). In some instances, the VL domain comprises kappa or lambda chains. In some instances, the constant domain is constant domain, light chain (CL) or constant domain, heavy chain (CH). In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the germline sequence in a first CDR region. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the germline sequence in a second CDR region. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the germline sequence in a third CDR region. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the germline sequence in a first CDR region of a heavy chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the germline sequence in a second CDR region of a heavy chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the germline sequence in a third CDR region of a heavy chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the germline sequence in a first CDR region of a light chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the germline sequence in a second CDR region of a light chain. In some instances, sequences generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from the germline sequence in a third CDR region of a light chain. In some instances, a first CDR region is CDR1. In some instances, a second CDR region is CDR2. In some instances, a third CDR region is CDR3.

VHH Libraries

Provided herein are methods, compositions, and systems for generation of antibodies or antibody fragments. In some instances, the antibodies or antibody fragments are single domain antibodies. Methods, compositions, and systems described herein for the optimization of antibodies comprise a ratio-variant approach that mirror the natural diversity of antibody sequences. In some instances, libraries of optimized antibodies comprise variant antibody sequences. In some instances, the variant antibody sequences are designed comprising variant CDR regions. In some instances, the variant antibody sequences comprising variant CDR regions are generated by shuffling the natural CDR sequences in a llama, humanized, or chimeric framework. In some instances, such libraries are synthesized, cloned into expression vectors, and translation products (antibodies) evaluated for activity. In some instances, fragments of sequences are synthesized and subsequently assembled. In some instances, expression vectors are used to display and enrich desired antibodies, such as phage display. In some instances, the phage vector is a Fab phagemid vector. Selection pressures used during enrichment in some instances includes, but is not limited to, binding affinity, toxicity, immunological tolerance, stability, receptor-ligand competition, or developability. Such expression vectors allow antibodies with specific properties to be selected (“panning”), and subsequent propagation or amplification of such sequences enriches the library with these sequences. Panning rounds can be repeated any number of times, such as 1, 2, 3, 4, 5, 6, 7, or more than 7 rounds. In some instances, each round of panning involves a number of washes. In some instances, each round of panning involves at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more than 16 washes.

Described herein are methods and systems of in-silico library design. Libraries as described herein, in some instances, are designed based on a database comprising a variety of antibody sequences. In some instances, the database comprises a plurality of variant antibody sequences against various targets. In some instances, the database comprises at least 100, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, or more than 5000 antibody sequences. An exemplary database is an iCAN database. In some instances, the database comprises naïve and memory B-cell receptor sequences. In some instances, the naïve and memory B-cell receptor sequences are human, mouse, or primate sequences. In some instances, the naïve and memory B-cell receptor sequences are human sequences. In some instances, the database is analyzed for position specific variation. In some instances, antibodies described herein comprise position specific variations in CDR regions. In some instances, the CDR regions comprise multiple sites for variation.

Described herein are libraries comprising variation in a CDR region. In some instances, the CDR is CDR1, CDR2, or CDR3 of a variable heavy chain. In some instances, the CDR is CDR1, CDR2, or CDR3 of a variable light chain. In some instances, the libraries comprise multiple variants encoding for CDR1, CDR2, or CDR3. In some instances, the libraries as described herein encode for at least 50, 100, 200, 300, 400, 500, 1000, 1200, 1500, 1700, 2000, 2500, 3000, 3500, 4000, 4500, 5000, or more than 5000 CDR1 sequences. In some instances, the libraries as described herein encode for at least 50, 100, 200, 300, 400, 500, 1000, 1200, 1500, 1700, 2000, 2500, 3000, 3500, 4000, 4500, 5000, or more than 5000 CDR2 sequences. In some instances, the libraries as described herein encode for at least 50, 100, 200, 300, 400, 500, 1000, 1200, 1500, 1700, 2000, 2500, 3000, 3500, 4000, 4500, 5000, or more than 5000 CDR3 sequences. In-silico antibodies libraries are in some instances synthesized, assembled, and enriched for desired sequences.

Following synthesis of CDR1 variants, CDR2 variants, and CDR3 variants, in some instances, the CDR1 variants, the CDR2 variants, and the CDR3 variants are shuffled to generate a diverse library. In some instances, the diversity of the libraries generated by methods described herein have a theoretical diversity of at least or about 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², 10¹³, 10¹⁴, 10¹⁵, 10¹⁶, 10¹⁷, 10¹⁸, or more than 10¹⁸ sequences. In some instances, the library has a final library diversity of at least or about 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², 10¹³, 10¹⁴, 10¹⁵, 10¹⁶, 10¹⁷, 10¹⁸, or more than 10¹⁸ sequences.

The germline sequences corresponding to a variant sequence may also be modified to generate sequences in a library. For example, sequences generated by methods described herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more than 16 mutations or variants from the germline sequence. In some instances, sequences generated comprise no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or no more than 18 mutations or variants from the germline sequence. In some instances, sequences generated comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or about 18 mutations or variants relative to the germline sequence.

Coronavirus Antibody Libraries

Provided herein are libraries generated from antibody optimization methods described herein. Antibodies described herein result in improved functional activity, structural stability, expression, specificity, or a combination thereof.

Provided herein are methods and compositions relating to SARS-CoV-2 binding libraries comprising nucleic acids encoding for a SARS-CoV-2 antibody. Further provided herein are methods and compositions relating to ACE2 binding libraries comprising nucleic acids encoding for an ACE2 antibody. Such methods and compositions in some instances are generated by the antibody optimization methods and systems described herein. Libraries as described herein may be further variegated to provide for variant libraries comprising nucleic acids each encoding for a predetermined variant of at least one predetermined reference nucleic acid sequence. Further described herein are protein libraries that may be generated when the nucleic acid libraries are translated. In some instances, nucleic acid libraries as described herein are transferred into cells to generate a cell library. Also provided herein are downstream applications for the libraries synthesized using methods described herein. Downstream applications include identification of variant nucleic acids or protein sequences with enhanced biologically relevant functions, e.g., improved stability, affinity, binding, functional activity, and for the treatment or prevention of an infection caused by a coronavirus such as SARS-CoV-2.

In some instances, an antibody or antibody fragment described herein comprises a sequence of any one of SEQ ID NOs: 1-2668. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a sequence of any one of SEQ ID NOs: 1-2668. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a sequence of any one of SEQ ID NOs: 1-2668. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a sequence of any one of SEQ ID NOs: 1-2668. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a sequence of any one of SEQ ID NOs: 1-2668.

In some instances, an antibody or antibody fragment described herein comprises a CDRH1 sequence of any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a CDRH1 sequence of any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a CDRH1 sequence of any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a CDRH1 sequence of any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a CDRH1 sequence of any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575. In some instances, an antibody or antibody fragment described herein comprises a CDRH2 sequence of any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a CDRH2 sequence of any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a CDRH2 sequence of any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a CDRH2 sequence of any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a CDRH2 sequence of any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604. In some instances, an antibody or antibody fragment described herein comprises a CDRH3 sequence of any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a CDRH3 sequence of any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a CDRH3 sequence of any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a CDRH3 sequence of any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a CDRH3 sequence of any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633.

In some instances, an antibody or antibody fragment described herein comprises a CDRH1 sequence of any one of SEQ ID NOs: 1-50, 779-919, 1344-1523, and 2381-2452. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a CDRH1 sequence of any one of SEQ ID NOs: 1-50, 779-919, 1344-1523, and 2381-2452. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a CDRH1 sequence of any one of SEQ ID NOs: 1-50, 779-919, 1344-1523, and 2381-2452. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a CDRH1 sequence of any one of SEQ ID NOs: 1-50, 779-919, 1344-1523, and 2381-2452. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a CDRH1 sequence of any one of SEQ ID NOs: 1-50, 779-919, 1344-1523, and 2381-2452. In some instances, an antibody or antibody fragment described herein comprises a CDRH2 sequence of any one of SEQ ID NOs: 51-100, 920-1061, 1524-1703, and 2453-2524. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a CDRH2 sequence of any one of SEQ ID NOs: 51-100, 920-1061, 1524-1703, and 2453-2524. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a CDRH2 sequence of any one of SEQ ID NOs: 51-100, 920-1061, 1524-1703, and 2453-2524. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a CDRH2 sequence of any one of SEQ ID NOs: 51-100, 920-1061, 1524-1703, and 2453-2524. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a CDRH2 sequence of any one of SEQ ID NOs: 51-100, 920-1061, 1524-1703, and 2453-2524. In some instances, an antibody or antibody fragment described herein comprises a CDRH3 sequence of any one of SEQ ID NOs: 101-150, 1062-1202, 1704-1883, and 2525-2596. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a CDRH3 sequence of any one of SEQ ID NOs: 101-150, 1062-1202, 1704-1883, and 2525-2596. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a CDRH3 sequence of any one of SEQ ID NOs: 101-150, 1062-1202, 1704-1883, and 2525-2596. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a CDRH3 sequence of any one of SEQ ID NOs: 101-150, 1062-1202, 1704-1883, and 2525-2596. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a CDRH3 sequence of any one of SEQ ID NOs: 101-150, 1062-1202, 1704-1883, and 2525-2596.

In some instances, an antibody or antibody fragment described herein comprises a CDRL1 sequence of any one of SEQ ID NOs: 196-210, 286-300, 412-438, and 634-662. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a CDRL1 sequence of any one of SEQ ID NOs: 196-210, 286-300, 412-438, and 634-662. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a CDRL1 sequence of any one of SEQ ID NOs: 196-210, 286-300, 412-438, and 634-662. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a CDRL1 sequence of any one of SEQ ID NOs: 1196-210, 286-300, 412-438, and 634-662. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a CDRL1 sequence of any one of SEQ ID NOs: 196-210, 286-300, 412-438, and 634-662. In some instances, an antibody or antibody fragment described herein comprises a CDRL2 sequence of any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a CDRL2 sequence of any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a CDRL2 sequence of any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a CDRL2 sequence of any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a CDRL2 sequence of any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691. In some instances, an antibody or antibody fragment described herein comprises a CDRL3 sequence of any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 80% identical to a CDRL3 sequence of any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 85% identical to a CDRL3 sequence of any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 90% identical to a CDRL3 sequence of any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720. In some instances, an antibody or antibody fragment described herein comprises a sequence that is at least 95% identical to a CDRL3 sequence of any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720.

In some embodiments, the antibody or antibody fragment comprising a variable domain, heavy chain region (VH) and a variable domain, light chain region (VL), wherein VH comprises complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein VL comprises complementarity determining regions CDRL1, CDRL2, and CDRL3, and wherein (a) an amino acid sequence of CDRH1 is as set forth in any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575; (b) an amino acid sequence of CDRH2 is as set forth in any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604; (c) an amino acid sequence of CDRH3 is as set forth in any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633; (d) an amino acid sequence of CDRL1 is as set forth in any one of SEQ ID NOs: 196-210, 286-300, 412-438, and 634-662; (e) an amino acid sequence of CDRL2 is as set forth in any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691; and (f) an amino acid sequence of CDRL3 is as set forth in any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720. In some embodiments, the antibody or antibody fragment comprising a variable domain, heavy chain region (VH) and a variable domain, light chain region (VL), wherein VH comprises complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein VL comprises complementarity determining regions CDRL1, CDRL2, and CDRL3, and wherein (a) an amino acid sequence of CDRH1 is at least or about 80%, 85%, 90%, or 95% identical to any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575; (b) an amino acid sequence of CDRH2 is at least or about 80%, 85%, 90%, or 95% identical to any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604; (c) an amino acid sequence of CDRH3 is at least or about 80%, 85%, 90%, or 95% identical to any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633; (d) an amino acid sequence of CDRL1 is at least or about 80%, 85%, 90%, or 95% identical to any one of SEQ ID NOs: 196-210, 286-300, 412-438, and 634-662; (e) an amino acid sequence of CDRL2 is at least or about 80%, 85%, 90%, or 95% identical to any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691; and (f) an amino acid sequence of CDRL3 is at least or about 80%, 85%, 90%, or 95% identical to any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720.

Described herein, in some embodiments, are antibodies or antibody fragments comprising a variable domain, heavy chain region (VH) and a variable domain, light chain region (VL), wherein the VH comprises an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 493-519 and 721-749, and wherein the VL comprises an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 520-546 and 750-778. In some instances, the antibodies or antibody fragments comprise VH comprising at least or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 493-519 and 721-749, and VL comprising at least or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 520-546 and 750-778.

Described herein, in some embodiments, are antibodies or antibody fragments comprising a variable domain, heavy chain region (VH), wherein the VH comprises an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 1884-2063, 2302-2380, and 2597-2668. In some instances, the antibodies or antibody fragments comprise a heavy chain variable domain comprising at least or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 1884-2063, 2302-2380, and 2597-2668.

The term “sequence identity” means that two polynucleotide sequences are identical (i.e., on a nucleotide-by-nucleotide basis) over the window of comparison. The term “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

The term “homology” or “similarity” between two proteins is determined by comparing the amino acid sequence and its conserved amino acid substitutes of one protein sequence to the second protein sequence. Similarity may be determined by procedures which are well-known in the art, for example, a BLAST program (Basic Local Alignment Search Tool at the National Center for Biological Information).

Provided herein are libraries comprising nucleic acids encoding for SARS-CoV-2 antibodies. Antibodies described herein allow for improved stability for a range of SARS-CoV-2 or ACE2 binding domain encoding sequences. In some instances, the binding domain encoding sequences are determined by interactions between SARS-CoV-2 and ACE2.

Sequences of binding domains based on surface interactions between SARS-CoV-2 and ACE2 are analyzed using various methods. For example, multispecies computational analysis is performed. In some instances, a structure analysis is performed. In some instances, a sequence analysis is performed. Sequence analysis can be performed using a database known in the art. Non-limiting examples of databases include, but are not limited to, NCBI BLAST (blast.ncbi.nlm.nih.gov/Blast.cgi), UCSC Genome Browser (genome.ucsc.edu/), UniProt (www.uniprot.org/), and IUPHAR/BPS Guide to PHARMACOLOGY (guidetopharmacology.org/).

Described herein are SARS-CoV-2 or ACE2 binding domains designed based on sequence analysis among various organisms. For example, sequence analysis is performed to identify homologous sequences in different organisms. Exemplary organisms include, but are not limited to, mouse, rat, equine, sheep, cow, primate (e.g., chimpanzee, baboon, gorilla, orangutan, monkey), dog, cat, pig, donkey, rabbit, fish, fly, and human. In some instances, homologous sequences are identified in the same organism, across individuals.

Following identification of SARS-CoV-2 or ACE2 binding domains, libraries comprising nucleic acids encoding for the SARS-CoV-2 or ACE2 binding domains may be generated. In some instances, libraries of SARS-CoV-2 or ACE2 binding domains comprise sequences of SARS-CoV-2 or ACE2 binding domains designed based on conformational ligand interactions, peptide ligand interactions, small molecule ligand interactions, extracellular domains of SARS-CoV-2 or ACE2, or antibodies that target SARS-CoV-2 or ACE2. Libraries of SARS-CoV-2 or ACE2 binding domains may be translated to generate protein libraries. In some instances, libraries of SARS-CoV-2 or ACE2 binding domains are translated to generate peptide libraries, immunoglobulin libraries, derivatives thereof, or combinations thereof. In some instances, libraries of SARS-CoV-2 or ACE2 binding domains are translated to generate protein libraries that are further modified to generate peptidomimetic libraries. In some instances, libraries of SARS-CoV-2 or ACE2 binding domains are translated to generate protein libraries that are used to generate small molecules.

Methods described herein provide for synthesis of libraries of SARS-CoV-2 or ACE2 binding domains comprising nucleic acids each encoding for a predetermined variant of at least one predetermined reference nucleic acid sequence. In some cases, the predetermined reference sequence is a nucleic acid sequence encoding for a protein, and the variant library comprises sequences encoding for variation of at least a single codon such that a plurality of different variants of a single residue in the subsequent protein encoded by the synthesized nucleic acid are generated by standard translation processes. In some instances, the libraries of SARS-CoV-2 or ACE2 binding domains comprise varied nucleic acids collectively encoding variations at multiple positions. In some instances, the variant library comprises sequences encoding for variation of at least a single codon in a SARS-CoV-2 or ACE2 binding domain. In some instances, the variant library comprises sequences encoding for variation of multiple codons in a SARS-CoV-2 or ACE2 binding domain. An exemplary number of codons for variation include, but are not limited to, at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 225, 250, 275, 300, or more than 300 codons.

Methods described herein provide for synthesis of libraries comprising nucleic acids encoding for the SARS-CoV-2 or ACE2 binding domains, wherein the libraries comprise sequences encoding for variation of length of the SARS-CoV-2 or ACE2 binding domains. In some instances, the library comprises sequences encoding for variation of length of at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 225, 250, 275, 300, or more than 300 codons less as compared to a predetermined reference sequence. In some instances, the library comprises sequences encoding for variation of length of at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, or more than 300 codons more as compared to a predetermined reference sequence.

Following identification of SARS-CoV-2 or ACE2 binding domains, antibodies may be designed and synthesized to comprise the SARS-CoV-2 or ACE2 binding domains. Antibodies comprising SARS-CoV-2 or ACE2 binding domains may be designed based on binding, specificity, stability, expression, folding, or downstream activity. In some instances, the antibodies comprising SARS-CoV-2 or ACE2 binding domains enable contact with the SARS-CoV-2 or ACE2. In some instances, the antibodies comprising SARS-CoV-2 or ACE2 binding domains enables high affinity binding with the SARS-CoV-2 or ACE2. Exemplary amino acid sequences of SARS-CoV-2 or ACE2 binding domains comprise any one of SEQ ID NOs: 1-2668.

In some instances, the SARS-CoV-2 antibody comprises a binding affinity (e.g., K_(D)) to SARS-CoV-2 of less than 1 nM, less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 11 nm, less than 13.5 nM, less than 15 nM, less than 20 nM, less than 25 nM, or less than 30 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 1 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 1.2 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 2 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 5 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 10 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 13.5 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 15 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 20 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 25 nM. In some instances, the SARS-CoV-2 antibody comprises a K_(D) of less than 30 nM.

In some instances, the ACE2 antibody comprises a binding affinity (e.g., K_(D)) to ACE2 of less than 1 nM, less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 11 nm, less than 13.5 nM, less than 15 nM, less than 20 nM, less than 25 nM, or less than 30 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 1 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 1.2 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 2 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 5 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 10 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 13.5 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 15 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 20 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 25 nM. In some instances, the ACE2 antibody comprises a K_(D) of less than 30 nM.

In some instances, the SARS-CoV-2 or ACE2 immunoglobulin is an agonist. In some instances, the SARS-CoV-2 or ACE2 immunoglobulin is an antagonist. In some instances, the SARS-CoV-2 or ACE2 immunoglobulin is an allosteric modulator. In some instances, the allosteric modulator is a negative allosteric modulator. In some instances, the allosteric modulator is a positive allosteric modulator. In some instances, the SARS-CoV-2 or ACE2 immunoglobulin results in agonistic, antagonistic, or allosteric effects at a concentration of at least or about 1 nM, 2 nM, 4 nM, 6 nM, 8 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 160 nM, 180 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1000 nM, or more than 1000 nM. In some instances, the SARS-CoV-2 or ACE2 immunoglobulin is a negative allosteric modulator. In some instances, the SARS-CoV-2 or ACE2 immunoglobulin is a negative allosteric modulator at a concentration of at least or about 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1 nM, 2 nM, 4 nM, 6 nM, 8 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, or more than 100 nM. In some instances, the SARS-CoV-2 or ACE2 immunoglobulin is a negative allosteric modulator at a concentration in a range of about 0.001 to about 100, 0.01 to about 90, about 0.1 to about 80, 1 to about 50, about 10 to about 40 nM, or about 1 to about 10 nM. In some instances, the SARS-CoV-2 or ACE2 immunoglobulin comprises an EC50 or IC50 of at least or about 0.001, 0.0025, 0.005, 0.01, 0.025, 0.05, 0.06, 0.07, 0.08, 0.9, 0.1, 0.5, 1, 2, 3, 4, 5, 6, or more than 6 nM. In some instances, the SARS-CoV-2 or ACE2 immunoglobulin comprises an EC50 or IC50 of at least or about 1 nM, 2 nM, 4 nM, 6 nM, 8 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, or more than 100 nM.

In some instances, the affinity of the SARS-CoV-2 or ACE2 antibody generated by methods as described herein is at least or about 1.5×, 2.0×, 5×, 10×, 20×, 30×, 40×, 50×, 60×, 70×, 80×, 90×, 100×, 200×, or more than 200× improved binding affinity as compared to a comparator antibody. In some instances, the SARS-CoV-2 or ACE2 antibody generated by methods as described herein is at least or about 1.5×, 2.0×, 5×, 10×, 20×, 30×, 40×, 50×, 60×, 70×, 80×, 90×, 100×, 200×, or more than 200× improved function as compared to a comparator antibody. In some instances, the comparator antibody is an antibody with similar structure, sequence, or antigen target.

Provided herein are SARS-CoV-2 or ACE2 binding libraries comprising nucleic acids encoding for antibodies comprising SARS-CoV-2 or ACE2 binding domains comprise variation in domain type, domain length, or residue variation. In some instances, the domain is a region in the antibody comprising the SARS-CoV-2 or ACE2 binding domains. For example, the region is the VH, CDRH3, or VL domain. In some instances, the domain is the SARS-CoV-2 or ACE2 binding domain.

Methods described herein provide for synthesis of a SARS-CoV-2 or ACE21 binding library of nucleic acids each encoding for a predetermined variant of at least one predetermined reference nucleic acid sequence. In some cases, the predetermined reference sequence is a nucleic acid sequence encoding for a protein, and the variant library comprises sequences encoding for variation of at least a single codon such that a plurality of different variants of a single residue in the subsequent protein encoded by the synthesized nucleic acid are generated by standard translation processes. In some instances, the SARS-CoV-2 or ACE2 binding library comprises varied nucleic acids collectively encoding variations at multiple positions. In some instances, the variant library comprises sequences encoding for variation of at least a single codon of a VH or VL domain. In some instances, the variant library comprises sequences encoding for variation of at least a single codon in a SARS-CoV-2 or ACE2 binding domain. For example, at least one single codon of a SARS-CoV-2 or ACE2 binding domain is varied. In some instances, the variant library comprises sequences encoding for variation of multiple codons of a VH or VL domain. In some instances, the variant library comprises sequences encoding for variation of multiple codons in a SARS-CoV-2 or ACE2 binding domain. An exemplary number of codons for variation include, but are not limited to, at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 225, 250, 275, 300, or more than 300 codons.

Methods described herein provide for synthesis of a SARS-CoV-2 or ACE2 binding library of nucleic acids each encoding for a predetermined variant of at least one predetermined reference nucleic acid sequence, wherein the SARS-CoV-2 or ACE2 binding library comprises sequences encoding for variation of length of a domain. In some instances, the domain is VH or VL domain. In some instances, the domain is the SARS-CoV-2 or ACE2 binding domain. In some instances, the library comprises sequences encoding for variation of length of at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 225, 250, 275, 300, or more than 300 codons less as compared to a predetermined reference sequence. In some instances, the library comprises sequences encoding for variation of length of at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, or more than 300 codons more as compared to a predetermined reference sequence.

Provided herein are SARS-CoV-2 or ACE2 binding libraries comprising nucleic acids encoding for antibodies comprising SARS-CoV-2 or ACE2 binding domains, wherein the SARS-CoV-2 or ACE2 binding libraries are synthesized with various numbers of fragments. In some instances, the fragments comprise the VH or VL domain. In some instances, the SARS-CoV-2 or ACE2 binding libraries are synthesized with at least or about 2 fragments, 3 fragments, 4 fragments, 5 fragments, or more than 5 fragments. The length of each of the nucleic acid fragments or average length of the nucleic acids synthesized may be at least or about 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, or more than 600 base pairs. In some instances, the length is about 50 to 600, 75 to 575, 100 to 550, 125 to 525, 150 to 500, 175 to 475, 200 to 450, 225 to 425, 250 to 400, 275 to 375, or 300 to 350 base pairs.

SARS-CoV-2 or ACE2 binding libraries comprising nucleic acids encoding for antibodies comprising SARS-CoV-2 or ACE2 binding domains as described herein comprise various lengths of amino acids when translated. In some instances, the length of each of the amino acid fragments or average length of the amino acid synthesized may be at least or about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, or more than 150 amino acids. In some instances, the length of the amino acid is about 15 to 150, 20 to 145, 25 to 140, 30 to 135, 35 to 130, 40 to 125, 45 to 120, 50 to 115, 55 to 110, 60 to 110, 65 to 105, 70 to 100, or 75 to 95 amino acids. In some instances, the length of the amino acid is about 22 to about 75 amino acids.

SARS-CoV-2 or ACE2 binding libraries comprising de novo synthesized variant sequences encoding for antibodies comprising SARS-CoV-2 or ACE2 binding domains comprise a number of variant sequences. In some instances, a number of variant sequences is de novo synthesized for a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, VL, VH, or a combination thereof. In some instances, a number of variant sequences is de novo synthesized for framework element 1 (FW1), framework element 2 (FW2), framework element 3 (FW3), or framework element 4 (FW4). In some instances, a number of variant sequences are de novo synthesized for a SARS-CoV-2 or ACE2 binding domain. The number of variant sequences may be at least or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or more than 500 sequences. In some instances, the number of variant sequences is about 10 to 300, 25 to 275, 50 to 250, 75 to 225, 100 to 200, or 125 to 150 sequences.

SARS-CoV-2 or ACE2 binding libraries comprising de novo synthesized variant sequences encoding for antibodies comprising SARS-CoV-2 or ACE2 binding domains comprise improved diversity. In some instances, variants include affinity maturation variants. Alternatively or in combination, variants include variants in other regions of the antibody including, but not limited to, CDRH1, CDRH2, CDRL1, CDRL2, and CDRL3. In some instances, the number of variants of the SARS-CoV-2 or ACE2 binding libraries is least or about 10⁴, 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², 10¹³, 10¹⁴ or more than 10¹⁴ non-identical sequences.

Following synthesis of SARS-CoV-2 or ACE2 binding libraries comprising nucleic acids encoding antibodies comprising SARS-CoV-2 or ACE2 binding domains, libraries may be used for screening and analysis. For example, libraries are assayed for library displayability and panning. In some instances, displayability is assayed using a selectable tag. Exemplary tags include, but are not limited to, a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, an affinity tag or other labels or tags that are known in the art. In some instances, the tag is histidine, polyhistidine, myc, hemagglutinin (HA), or FLAG. For example, SARS-CoV-2 or ACE2 binding libraries comprise nucleic acids encoding antibodies comprising SARS-CoV-2 or ACE2 binding domains with multiple tags such as GFP, FLAG, and Lucy as well as a DNA barcode. In some instances, libraries are assayed by sequencing using various methods including, but not limited to, single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis.

As used herein, the term antibody will be understood to include proteins having the characteristic two-armed, Y-shape of a typical antibody molecule as well as one or more fragments of an antibody that retain the ability to specifically bind to an antigen. Exemplary antibodies include, but are not limited to, a monoclonal antibody, a polyclonal antibody, a bi-specific antibody, a multispecific antibody, a grafted antibody, a human antibody, a humanized antibody, a synthetic antibody, a chimeric antibody, a camelized antibody, a single-chain Fvs (scFv) (including fragments in which the VL and VH are joined using recombinant methods by a synthetic or natural linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules, including single chain Fab and scFab), a single chain antibody, a Fab fragment (including monovalent fragments comprising the VL, VH, CL, and CH1 domains), a F(ab′)2 fragment (including bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region), a Fd fragment (including fragments comprising the VH and CH1 fragment), a Fv fragment (including fragments comprising the VL and VH domains of a single arm of an antibody), a single-domain antibody (dAb or sdAb) (including fragments comprising a VH domain), an isolated complementarity determining region (CDR), a diabody (including fragments comprising bivalent dimers such as two VL and VH domains bound to each other and recognizing two different antigens), a fragment comprised of only a single monomeric variable domain, disulfide-linked Fvs (sdFv), an intrabody, an anti-idiotypic (anti-Id) antibody, or ab antigen-binding fragments thereof. In some instances, the libraries disclosed herein comprise nucleic acids encoding for an antibody, wherein the antibody is a Fv antibody, including Fv antibodies comprised of the minimum antibody fragment which contains a complete antigen-recognition and antigen-binding site. In some embodiments, the Fv antibody consists of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association, and the three hypervariable regions of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. In some embodiments, the six hypervariable regions confer antigen-binding specificity to the antibody. In some embodiments, a single variable domain (or half of an Fv comprising only three hypervariable regions specific for an antigen, including single domain antibodies isolated from camelid animals comprising one heavy chain variable domain such as VHH antibodies or nanobodies) has the ability to recognize and bind antigen. In some instances, the libraries disclosed herein comprise nucleic acids encoding for an antibody, wherein the antibody is a single-chain Fv or scFv, including antibody fragments comprising a VH, a VL, or both a VH and VL domain, wherein both domains are present in a single polypeptide chain. In some embodiments, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains allowing the scFv to form the desired structure for antigen binding. In some instances, a scFv is linked to the Fc fragment or a VHH is linked to the Fc fragment (including minibodies). In some instances, the antibody comprises immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, e.g., molecules that contain an antigen binding site. Immunoglobulin molecules are of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG 1, IgG 2, IgG 3, IgG 4, IgA 1 and IgA 2) or subclass.

In some embodiments, the antibody is a multivalent antibody. In some embodiments, the antibody is a monovalent, bivalent, or multivalent antibody. In some instances, the antibody is monospecific, bispecific, or multispecific. In some embodiments, the antibody is monovalent monospecific, monovalent bispecific, monovalent multispecific, bivalent monospecific, bivalent bispecific, bivalent multispecific, multivalent monospecific, multivalent bispecific, multivalent multispecific. In some instances, the antibody is homodimeric, heterodimeric, or heterotrimeric.

In some embodiments, libraries comprise immunoglobulins that are adapted to the species of an intended therapeutic target. Generally, these methods include “mammalization” and comprises methods for transferring donor antigen-binding information to a less immunogenic mammal antibody acceptor to generate useful therapeutic treatments. In some instances, the mammal is mouse, rat, equine, sheep, cow, primate (e.g., chimpanzee, baboon, gorilla, orangutan, monkey), dog, cat, pig, donkey, rabbit, and human. In some instances, provided herein are libraries and methods for felinization and caninization of antibodies.

“Humanized” forms of non-human antibodies can be chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human antibody (recipient antibody) in which residues from one or more CDRs are replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. In some instances, these modifications are made to further refine antibody performance.

“Caninization” can comprise a method for transferring non-canine antigen-binding information from a donor antibody to a less immunogenic canine antibody acceptor to generate treatments useful as therapeutics in dogs. In some instances, caninized forms of non-canine antibodies provided herein are chimeric antibodies that contain minimal sequence derived from non-canine antibodies. In some instances, caninized antibodies are canine antibody sequences (“acceptor” or “recipient” antibody) in which hypervariable region residues of the recipient are replaced by hypervariable region residues from a non-canine species (“donor” antibody) such as mouse, rat, rabbit, cat, dogs, goat, chicken, bovine, horse, llama, camel, dromedaries, sharks, non-human primates, human, humanized, recombinant sequence, or an engineered sequence having the desired properties. In some instances, framework region (FR) residues of the canine antibody are replaced by corresponding non-canine FR residues. In some instances, caninized antibodies include residues that are not found in the recipient antibody or in the donor antibody. In some instances, these modifications are made to further refine antibody performance. The caninized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc) of a canine antibody.

“Felinization” can comprise a method for transferring non-feline antigen-binding information from a donor antibody to a less immunogenic feline antibody acceptor to generate treatments useful as therapeutics in cats. In some instances, felinized forms of non-feline antibodies provided herein are chimeric antibodies that contain minimal sequence derived from non-feline antibodies. In some instances, felinized antibodies are feline antibody sequences (“acceptor” or “recipient” antibody) in which hypervariable region residues of the recipient are replaced by hypervariable region residues from a non-feline species (“donor” antibody) such as mouse, rat, rabbit, cat, dogs, goat, chicken, bovine, horse, llama, camel, dromedaries, sharks, non-human primates, human, humanized, recombinant sequence, or an engineered sequence having the desired properties. In some instances, framework region (FR) residues of the feline antibody are replaced by corresponding non-feline FR residues. In some instances, felinized antibodies include residues that are not found in the recipient antibody or in the donor antibody. In some instances, these modifications are made to further refine antibody performance. The felinized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc) of a felinize antibody.

Methods as described herein may be used for optimization of libraries encoding a non-immunoglobulin. In some instances, the libraries comprise antibody mimetics. Exemplary antibody mimetics include, but are not limited to, anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, atrimers, DARPins, fynomers, Kunitz domain-based proteins, monobodies, anticalins, knottins, armadillo repeat protein-based proteins, and bicyclic peptides.

Libraries described herein comprising nucleic acids encoding for an antibody comprise variations in at least one region of the antibody. Exemplary regions of the antibody for variation include, but are not limited to, a complementarity-determining region (CDR), a variable domain, or a constant domain. In some instances, the CDR is CDR1, CDR2, or CDR3. In some instances, the CDR is a heavy domain including, but not limited to, CDRH1, CDRH2, and CDRH3. In some instances, the CDR is a light domain including, but not limited to, CDRL1, CDRL2, and CDRL3. In some instances, the variable domain is variable domain, light chain (VL) or variable domain, heavy chain (VH). In some instances, the VL domain comprises kappa or lambda chains. In some instances, the constant domain is constant domain, light chain (CL) or constant domain, heavy chain (CH).

Methods described herein provide for synthesis of libraries comprising nucleic acids encoding an antibody, wherein each nucleic acid encodes for a predetermined variant of at least one predetermined reference nucleic acid sequence. In some cases, the predetermined reference sequence is a nucleic acid sequence encoding for a protein, and the variant library comprises sequences encoding for variation of at least a single codon such that a plurality of different variants of a single residue in the subsequent protein encoded by the synthesized nucleic acid are generated by standard translation processes. In some instances, the antibody library comprises varied nucleic acids collectively encoding variations at multiple positions. In some instances, the variant library comprises sequences encoding for variation of at least a single codon of a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, VL, or VH domain. In some instances, the variant library comprises sequences encoding for variation of multiple codons of a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, VL, or VH domain. In some instances, the variant library comprises sequences encoding for variation of multiple codons of framework element 1 (FW1), framework element 2 (FW2), framework element 3 (FW3), or framework element 4 (FW4). An exemplary number of codons for variation include, but are not limited to, at least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 225, 250, 275, 300, or more than 300 codons.

In some instances, the at least one region of the antibody for variation is from heavy chain V-gene family, heavy chain D-gene family, heavy chain J-gene family, light chain V-gene family, or light chain J-gene family. In some instances, the light chain V-gene family comprises immunoglobulin kappa (IGK) gene or immunoglobulin lambda (IGL). Exemplary regions of the antibody for variation include, but are not limited to, IGHV1-18, IGHV1-69, IGHV1-8, IGHV3-21, IGHV3-23, IGHV3-30/33rn, IGHV3-28, IGHV1-69, IGHV3-74, IGHV4-39, IGHV4-59/61, IGKV1-39, IGKV1-9, IGKV2-28, IGKV3-11, IGKV3-15, IGKV3-20, IGKV4-1, IGLV1-51, IGLV2-14, IGLV1-40, and IGLV3-1. In some instances, the gene is IGHV1-69, IGHV3-30, IGHV3-23, IGHV3, IGHV1-46, IGHV3-7, IGHV1, or IGHV1-8. In some instances, the gene is IGHV1-69 and IGHV3-30. In some instances, the region of the antibody for variation is IGHJ3, IGHJ6, IGHJ, IGHJ4, IGHJ5, IGHJ2, or IGH1. In some instances, the region of the antibody for variation is IGHJ3, IGHJ6, IGHJ, or IGHJ4. In some instances, the at least one region of the antibody for variation is IGHV1-69, IGHV3-23, IGKV3-20, IGKV1-39, or combinations thereof. In some instances, the at least one region of the antibody for variation is IGHV1-69 and IGKV3-20, In some instances, the at least one region of the antibody for variation is IGHV1-69 and IGKV1-39. In some instances, the at least one region of the antibody for variation is IGHV3-23 and IGKV3-20. In some instances, the at least one region of the antibody for variation is IGHV3-23 and IGKV1-39.

Provided herein are libraries comprising nucleic acids encoding for antibodies, wherein the libraries are synthesized with various numbers of fragments. In some instances, the fragments comprise the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, VL, or VH domain. In some instances, the fragments comprise framework element 1 (FW1), framework element 2 (FW2), framework element 3 (FW3), or framework element 4 (FW4). In some instances, the antibody libraries are synthesized with at least or about 2 fragments, 3 fragments, 4 fragments, 5 fragments, or more than 5 fragments. The length of each of the nucleic acid fragments or average length of the nucleic acids synthesized may be at least or about 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, or more than 600 base pairs. In some instances, the length is about 50 to 600, 75 to 575, 100 to 550, 125 to 525, 150 to 500, 175 to 475, 200 to 450, 225 to 425, 250 to 400, 275 to 375, or 300 to 350 base pairs.

Libraries comprising nucleic acids encoding for antibodies as described herein comprise various lengths of amino acids when translated. In some instances, the length of each of the amino acid fragments or average length of the amino acid synthesized may be at least or about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, or more than 150 amino acids. In some instances, the length of the amino acid is about 15 to 150, 20 to 145, 25 to 140, 30 to 135, 35 to 130, 40 to 125, 45 to 120, 50 to 115, 55 to 110, 60 to 110, 65 to 105, 70 to 100, or 75 to 95 amino acids. In some instances, the length of the amino acid is about 22 amino acids to about 75 amino acids. In some instances, the antibodies comprise at least or about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, or more than 5000 amino acids.

A number of variant sequences for the at least one region of the antibody for variation are de novo synthesized using methods as described herein. In some instances, a number of variant sequences is de novo synthesized for CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, VL, VH, or combinations thereof. In some instances, a number of variant sequences is de novo synthesized for framework element 1 (FW1), framework element 2 (FW2), framework element 3 (FW3), or framework element 4 (FW4). The number of variant sequences may be at least or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or more than 500 sequences. In some instances, the number of variant sequences is at least or about 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, or more than 8000 sequences. In some instances, the number of variant sequences is about 10 to 500, 25 to 475, 50 to 450, 75 to 425, 100 to 400, 125 to 375, 150 to 350, 175 to 325, 200 to 300, 225 to 375, 250 to 350, or 275 to 325 sequences.

Variant sequences for the at least one region of the antibody, in some instances, vary in length or sequence. In some instances, the at least one region that is de novo synthesized is for CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, VL, VH, or combinations thereof. In some instances, the at least one region that is de novo synthesized is for framework element 1 (FW1), framework element 2 (FW2), framework element 3 (FW3), or framework element 4 (FW4). In some instances, the variant sequence comprises at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, or more than 50 variant nucleotides or amino acids as compared to wild-type. In some instances, the variant sequence comprises at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 additional nucleotides or amino acids as compared to wild-type. In some instances, the variant sequence comprises at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 less nucleotides or amino acids as compared to wild-type. In some instances, the libraries comprise at least or about 10¹, 10², 10³, 10⁴, 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, or more than 10¹⁰ variants.

Following synthesis of antibody libraries, antibody libraries may be used for screening and analysis. For example, antibody libraries are assayed for library displayability and panning. In some instances, displayability is assayed using a selectable tag. Exemplary tags include, but are not limited to, a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, an affinity tag or other labels or tags that are known in the art. In some instances, the tag is histidine, polyhistidine, myc, hemagglutinin (HA), or FLAG. In some instances, antibody libraries are assayed by sequencing using various methods including, but not limited to, single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. In some instances, antibody libraries are displayed on the surface of a cell or phage. In some instances, antibody libraries are enriched for sequences with a desired activity using phage display.

In some instances, the antibody libraries are assayed for functional activity, structural stability (e.g., thermal stable or pH stable), expression, specificity, or a combination thereof. In some instances, the antibody libraries are assayed for antibody capable of folding. In some instances, a region of the antibody is assayed for functional activity, structural stability, expression, specificity, folding, or a combination thereof. For example, a VH region or VL region is assayed for functional activity, structural stability, expression, specificity, folding, or a combination thereof.

In some instances, the affinity of antibodies or IgGs generated by methods as described herein is at least or about 1.5×, 2.0×, 5×, 10×, 20×, 30×, 40×, 50×, 60×, 70×, 80×, 90×, 100×, 200×, or more than 200× improved binding affinity as compared to a comparator antibody. In some instances, the affinity of antibodies or IgGs generated by methods as described herein is at least or about 1.5×, 2.0×, 5×, 10×, 20×, 30×, 40×, 50×, 60×, 70×, 80×, 90×, 100×, 200×, or more than 200× improved function as compared to a comparator antibody. In some instances, the comparator antibody is an antibody with similar structure, sequence, or antigen target.

Expression Systems

Provided herein are libraries comprising nucleic acids encoding for antibody comprising binding domains, wherein the libraries have improved specificity, stability, expression, folding, or downstream activity. In some instances, libraries described herein are used for screening and analysis.

Provided herein are libraries comprising nucleic acids encoding for antibody comprising binding domains, wherein the nucleic acid libraries are used for screening and analysis. In some instances, screening and analysis comprises in vitro, in vivo, or ex vivo assays. Cells for screening include primary cells taken from living subjects or cell lines. Cells may be from prokaryotes (e.g., bacteria and fungi) or eukaryotes (e.g., animals and plants). Exemplary animal cells include, without limitation, those from a mouse, rabbit, primate, and insect. In some instances, cells for screening include a cell line including, but not limited to, Chinese Hamster Ovary (CHO) cell line, human embryonic kidney (HEK) cell line, or baby hamster kidney (BHK) cell line. In some instances, nucleic acid libraries described herein may also be delivered to a multicellular organism. Exemplary multicellular organisms include, without limitation, a plant, a mouse, rabbit, primate, and insect.

Nucleic acid libraries described herein may be screened for various pharmacological or pharmacokinetic properties. In some instances, the libraries are screened using in vitro assays, in vivo assays, or ex vivo assays. For example, in vitro pharmacological or pharmacokinetic properties that are screened include, but are not limited to, binding affinity, binding specificity, and binding avidity. Exemplary in vivo pharmacological or pharmacokinetic properties of libraries described herein that are screened include, but are not limited to, therapeutic efficacy, activity, preclinical toxicity properties, clinical efficacy properties, clinical toxicity properties, immunogenicity, potency, and clinical safety properties.

Provided herein are nucleic acid libraries, wherein the nucleic acid libraries may be expressed in a vector. Expression vectors for inserting nucleic acid libraries disclosed herein may comprise eukaryotic or prokaryotic expression vectors. Exemplary expression vectors include, without limitation, mammalian expression vectors: pSF-CMV-NEO-NH2-PPT-3×FLAG, pSF-CMV-NEO-COOH-3×FLAG, pSF-CMV-PURO-NH2-GST-TEV, pSF-OXB20-COOH-TEV-FLAG(R)-6His, pCEP4 pDEST27, pSF-CMV-Ub-KrYFP, pSF-CMV-FMDV-daGFP, pEF1a-mCherry-N1 Vector, pEF1a-tdTomato Vector, pSF-CMV-FMDV-Hygro, pSF-CMV-PGK-Puro, pMCP-tag(m), and pSF-CMV-PURO-NH2-CMYC; bacterial expression vectors: pSF-OXB20-BetaGal,pSF-OXB20-Fluc, pSF-OXB20, and pSF-Tac; plant expression vectors: pRI 101-AN DNA and pCambia2301; and yeast expression vectors: pTYB21 and pKLAC2, and insect vectors: pAc5.1/V5-His A and pDEST8. In some instances, the vector is pcDNA3 or pcDNA3.1.

Described herein are nucleic acid libraries that are expressed in a vector to generate a construct comprising an antibody. In some instances, a size of the construct varies. In some instances, the construct comprises at least or about 500, 600, 700, 800, 900, 1000, 1100, 1300, 1400, 1500, 1600, 1700, 1800, 2000, 2400, 2600, 2800, 3000, 3200, 3400, 3600, 3800, 4000, 4200, 4400, 4600, 4800, 5000, 6000, 7000, 8000, 9000, 10000, or more than 10000 bases. In some instances, a the construct comprises a range of about 300 to 1,000, 300 to 2,000, 300 to 3,000, 300 to 4,000, 300 to 5,000, 300 to 6,000, 300 to 7,000, 300 to 8,000, 300 to 9,000, 300 to 10,000, 1,000 to 2,000, 1,000 to 3,000, 1,000 to 4,000, 1,000 to 5,000, 1,000 to 6,000, 1,000 to 7,000, 1,000 to 8,000, 1,000 to 9,000, 1,000 to 10,000, 2,000 to 3,000, 2,000 to 4,000, 2,000 to 5,000, 2,000 to 6,000, 2,000 to 7,000, 2,000 to 8,000, 2,000 to 9,000, 2,000 to 10,000, 3,000 to 4,000, 3,000 to 5,000, 3,000 to 6,000, 3,000 to 7,000, 3,000 to 8,000, 3,000 to 9,000, 3,000 to 10,000, 4,000 to 5,000, 4,000 to 6,000, 4,000 to 7,000, 4,000 to 8,000, 4,000 to 9,000, 4,000 to 10,000, 5,000 to 6,000, 5,000 to 7,000, 5,000 to 8,000, 5,000 to 9,000, 5,000 to 10,000, 6,000 to 7,000, 6,000 to 8,000, 6,000 to 9,000, 6,000 to 10,000, 7,000 to 8,000, 7,000 to 9,000, 7,000 to 10,000, 8,000 to 9,000, 8,000 to 10,000, or 9,000 to 10,000 bases.

Provided herein are libraries comprising nucleic acids encoding for antibodies, wherein the nucleic acid libraries are expressed in a cell. In some instances, the libraries are synthesized to express a reporter gene. Exemplary reporter genes include, but are not limited to, acetohydroxyacid synthase (AHAS), alkaline phosphatase (AP), beta galactosidase (LacZ), beta glucuronidase (GUS), chloramphenicol acetyltransferase (CAT), green fluorescent protein (GFP), red fluorescent protein (RFP), yellow fluorescent protein (YFP), cyan fluorescent protein (CFP), cerulean fluorescent protein, citrine fluorescent protein, orange fluorescent protein, cherry fluorescent protein, turquoise fluorescent protein, blue fluorescent protein, horseradish peroxidase (HRP), luciferase (Luc), nopaline synthase (NOS), octopine synthase (OCS), luciferase, and derivatives thereof. Methods to determine modulation of a reporter gene are well known in the art, and include, but are not limited to, fluorometric methods (e.g. fluorescence spectroscopy, Fluorescence Activated Cell Sorting (FACS), fluorescence microscopy), and antibiotic resistance determination.

Diseases and Disorders

Provided herein are SARS-CoV-2 or ACE2 binding libraries comprising nucleic acids encoding for antibodies comprising SARS-CoV-2 or ACE2 binding domains may have therapeutic effects. In some instances, the SARS-CoV-2 or ACE2 binding libraries result in protein when translated that is used to treat a disease or disorder. In some instances, the protein is an immunoglobulin. In some instances, the protein is a peptidomimetic. In some instances, the disease or disorder is a viral infection caused by SARS-CoV-2. In some instances, the disease or disorder is a respiratory disease or disorder caused by SARS-CoV-2.

SARS-CoV-2 or ACE2 variant antibody libraries as described herein may be used to treat SARS-CoV-2. In some embodiments, the SARS-CoV-2 or ACE2 variant antibody libraries are used to treat or prevent symptoms of SARS-CoV-2. These symptoms include, but are not limited to, fever, chills, cough, fatigue, headaches, loss of taste, loss of smell, nausea, vomiting, muscle weakness, sleep difficulties, anxiety, and depression. In some embodiments, the SARS-CoV-2 or ACE2 variant antibody libraries are used to treat a subject who has symptoms for an extended period of time. In some embodiments, the subject has symptoms for an extended period of time after testing negative for SARS-CoV-2. In some embodiments, the subject has symptoms for an extended period of time including at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or more than 1 year.

In some instances, the subject is a mammal. In some instances, the subject is a mouse, rabbit, dog, or human. Subjects treated by methods described herein may be infants, adults, or children. Pharmaceutical compositions comprising antibodies or antibody fragments as described herein may be administered intravenously or subcutaneously. In some instances, a pharmaceutical composition comprises an antibody or antibody fragment described herein comprising a CDRH1 sequence of any one of SEQ ID NOs: 1-50, 779-919, 1344-1523, and 2381-2452. In some instances, a pharmaceutical composition comprises an antibody or antibody fragment described herein comprising a CDRH2 sequence of any one of SEQ ID NOs: 51-100, 920-1061, 1524-1703, and 2453-2524 In some instances, a pharmaceutical composition comprises an antibody or antibody fragment described herein comprising a CDRH3 sequence of any one of SEQ ID NOs: 101-150, 1062-1202, 1704-1883, and 2525-2596. In some instances, a pharmaceutical composition comprises an antibody or antibody fragment described herein comprising a variable domain, heavy chain region (VH) and a variable domain, light chain region (VL), wherein VH comprises complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein VL comprises complementarity determining regions CDRL1, CDRL2, and CDRL3, and wherein (a) an amino acid sequence of CDRH1 is as set forth in any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575; (b) an amino acid sequence of CDRH2 is as set forth in any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604; (c) an amino acid sequence of CDRH3 is as set forth in any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633; (d) an amino acid sequence of CDRL1 is as set forth in any one of SEQ ID NOs: 196-210, 286-300, 412-438, and 634-662; (e) an amino acid sequence of CDRL2 is as set forth in any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691; and (f) an amino acid sequence of CDRL3 is as set forth in any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720. In some instances, a pharmaceutical composition comprises an antibody or antibody fragment described herein comprising a VH comprising at least or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 493-519 and 721-749, and VL comprising at least or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 520-546 and 750-778. In some instances, a pharmaceutical composition comprises an antibody or antibody fragment described herein comprising a heavy chain variable domain comprising at least or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs: 1918-2058, 2599-2778, and 3095-3173.

SARS-CoV-2 or ACE2 antibodies as described herein may confer immunity after exposure to SARS-CoV-2 or ACE2 antibodies. In some embodiments, the SARS-CoV-2 or ACE2 antibodies described herein are used for passive immunization of a subject. In some instances, the subject is actively immunized after exposure to SARS-CoV-2 or ACE2 antibodies followed by exposure to SARS-CoV-2. In some embodiments, SARS-CoV-2 or ACE2 antibodies are derived from a subject who has recovered from SARS-CoV-2.

In some embodiments, the immunity occurs at least about 30 minutes, 1 hour, 5 hours, 10 hours, 16 hours, 20 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or more than 2 weeks after exposure to SARS-CoV-2 or ACE2 antibodies. In some instances, the immunity lasts for at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5 years after exposure to SARS-CoV-2 or ACE2 antibodies.

In some embodiments, the subject receives the SARS-CoV-2 or ACE2 antibodies prior to exposure to SARS-CoV-2. In some embodiments, the subject receives the SARS-CoV-2 or ACE2 antibodies at least about 30 minutes, 1 hour, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5 years prior to exposure to SARS-CoV-2. In some embodiments, the subject receives the SARS-CoV-2 or ACE2 antibodies after exposure to SARS-CoV-2. In some embodiments, the subject receives the SARS-CoV-2 or ACE2 antibodies at least about 30 minutes, 1 hour, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5 years after exposure to SARS-CoV-2.

SARS-CoV-2 or ACE2 antibodies described herein may be administered through various routes. The administration may, depending on the composition being administered, for example, be oral, pulmonary, intravenous, intraperitoneal, intramuscular, intracavity, subcutaneous, or transdermal.

Described herein are compositions or pharmaceutical compositions comprising SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof that comprise various dosages of the antibodies or antibody fragment. In some instances, the dosage is ranging from about 1 to 25 mg/kg, from about 1 to 50 mg/kg, from about 1 to 80 mg/kg, from about 1 to about 100 mg/kg, from about 5 to about 100 mg/kg, from about 5 to about 80 mg/kg, from about 5 to about 60 mg/kg, from about 5 to about 50 mg/kg or from about 5 to about 500 mg/kg which can be administered in single or multiple doses. In some instances, the dosage is administered in an amount of about 0.01 mg/kg, about 0.05 mg/kg, about 0.10 mg/kg, about 0.25 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 105 mg/kg, about 110 mg/kg, about 115 mg/kg, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 240, about 250, about 260, about 270, about 275, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360 mg/kg, about 370 mg/kg, about 380 mg/kg, about 390 mg/kg, about 400 mg/kg, 410 mg/kg, about 420 mg/kg, about 430 mg/kg, about 440 mg/kg, about 450 mg/kg, about 460 mg/kg, about 470 mg/kg, about 480 mg/kg, about 490 mg/kg, or about 500 mg/kg.

SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof described herein, in some embodiments, improve disease severity. In some embodiments, the SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof improve disease severity at a dose level of about 0.01 mg/kg, about 0.05 mg/kg, about 0.10 mg/kg, about 0.25 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 20 mg/kg. In some embodiments, the SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof improve disease severity at a dose level of about 1 mg/kg, about 5 mg/kg, or about 10 mg/kg. In some embodiments, disease severity is determined by percent weight loss. In some embodiments, the SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof protects against weight loss at a dose level of about 0.01 mg/kg, about 0.05 mg/kg, about 0.10 mg/kg, about 0.25 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 20 mg/kg. In some embodiments, the SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof protects against weight loss at a dose level of about 1 mg/kg, about 5 mg/kg, or about 10 mg/kg. In some embodiments, SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof

Variant Libraries

Codon Variation

Variant nucleic acid libraries described herein may comprise a plurality of nucleic acids, wherein each nucleic acid encodes for a variant codon sequence compared to a reference nucleic acid sequence. In some instances, each nucleic acid of a first nucleic acid population contains a variant at a single variant site. In some instances, the first nucleic acid population contains a plurality of variants at a single variant site such that the first nucleic acid population contains more than one variant at the same variant site. The first nucleic acid population may comprise nucleic acids collectively encoding multiple codon variants at the same variant site. The first nucleic acid population may comprise nucleic acids collectively encoding up to 19 or more codons at the same position. The first nucleic acid population may comprise nucleic acids collectively encoding up to 60 variant triplets at the same position, or the first nucleic acid population may comprise nucleic acids collectively encoding up to 61 different triplets of codons at the same position. Each variant may encode for a codon that results in a different amino acid during translation. Table 1 provides a listing of each codon possible (and the representative amino acid) for a variant site.

TABLE 1 List of codons and amino acids One Three letter letter Amino Acids code code Codons Alanine A Ala GCA GCC GCG GCT Cysteine C Cys TGC TGT Aspartic D Asp GAC GAT acid Glutamic E Glu GAA GAG acid Phenylalanine F Phe TTC TTT Glycine G Gly GGA GGC GGG GGT Histidine H His CAC CAT Isoleucine I Iso ATA ATC ATT Lysine K Lys AAA AAG Leucine L Leu TTA TTG CTA CTC CTG CTT Methionine M Met ATG Asparagine N Asn AAC AAT Proline P Pro CCA CCC CCG CCT Glutamine Q Gln CAA CAG Arginine R Arg AGA AGG CGA CGC CGG CGT Serine S Ser AGC AGT TCA TCC TCG TCT Threonine T Thr ACA ACC ACG ACT Valine V Val GTA GTC GTG GTT Tryptophan W Trp TGG Tyrosine Y Tyr TAC TAT

A nucleic acid population may comprise varied nucleic acids collectively encoding up to 20 codon variations at multiple positions. In such cases, each nucleic acid in the population comprises variation for codons at more than one position in the same nucleic acid. In some instances, each nucleic acid in the population comprises variation for codons at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more codons in a single nucleic acid. In some instances, each variant long nucleic acid comprises variation for codons at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more codons in a single long nucleic acid. In some instances, the variant nucleic acid population comprises variation for codons at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more codons in a single nucleic acid. In some instances, the variant nucleic acid population comprises variation for codons in at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more codons in a single long nucleic acid.

Highly Parallel Nucleic Acid Synthesis

Provided herein is a platform approach utilizing miniaturization, parallelization, and vertical integration of the end-to-end process from polynucleotide synthesis to gene assembly within nanowells on silicon to create a revolutionary synthesis platform. Devices described herein provide, with the same footprint as a 96-well plate, a silicon synthesis platform is capable of increasing throughput by a factor of up to 1,000 or more compared to traditional synthesis methods, with production of up to approximately 1,000,000 or more polynucleotides, or 10,000 or more genes in a single highly-parallelized run.

With the advent of next-generation sequencing, high resolution genomic data has become an important factor for studies that delve into the biological roles of various genes in both normal biology and disease pathogenesis. At the core of this research is the central dogma of molecular biology and the concept of “residue-by-residue transfer of sequential information.” Genomic information encoded in the DNA is transcribed into a message that is then translated into the protein that is the active product within a given biological pathway.

Another exciting area of study is on the discovery, development and manufacturing of therapeutic molecules focused on a highly-specific cellular target. High diversity DNA sequence libraries are at the core of development pipelines for targeted therapeutics. Gene variants are used to express proteins in a design, build, and test protein engineering cycle that ideally culminates in an optimized gene for high expression of a protein with high affinity for its therapeutic target. As an example, consider the binding pocket of a receptor. The ability to test all sequence permutations of all residues within the binding pocket simultaneously will allow for a thorough exploration, increasing chances of success. Saturation mutagenesis, in which a researcher attempts to generate all possible mutations or variants at a specific site within the receptor, represents one approach to this development challenge. Though costly and time and labor-intensive, it enables each variant to be introduced into each position. In contrast, combinatorial mutagenesis, where a few selected positions or short stretch of DNA may be modified extensively, generates an incomplete repertoire of variants with biased representation.

To accelerate the drug development pipeline, a library with the desired variants available at the intended frequency in the right position available for testing—in other words, a precision library, enables reduced costs as well as turnaround time for screening. Provided herein are methods for synthesizing nucleic acid synthetic variant libraries which provide for precise introduction of each intended variant at the desired frequency. To the end user, this translates to the ability to not only thoroughly sample sequence space but also be able to query these hypotheses in an efficient manner, reducing cost and screening time. Genome-wide editing can elucidate important pathways, libraries where each variant and sequence permutation can be tested for optimal functionality, and thousands of genes can be used to reconstruct entire pathways and genomes to re-engineer biological systems for drug discovery.

Ina first example, a drug itself can be optimized using methods described herein. For example, to improve a specified function of an antibody, a variant polynucleotide library encoding for a portion of the antibody is designed and synthesized. A variant nucleic acid library for the antibody can then be generated by processes described herein (e.g., PCR mutagenesis followed by insertion into a vector). The antibody is then expressed in a production cell line and screened for enhanced activity. Example screens include examining modulation in binding affinity to an antigen, stability, or effector function (e.g., ADCC, complement, or apoptosis). Exemplary regions to optimize the antibody include, without limitation, the Fc region, Fab region, variable region of the Fab region, constant region of the Fab region, variable domain of the heavy chain or light chain (V_(H) or V_(L)), and specific complementarity-determining regions (CDRs) of V_(H) or VL.

Nucleic acid libraries synthesized by methods described herein may be expressed in various cells associated with a disease state. Cells associated with a disease state include cell lines, tissue samples, primary cells from a subject, cultured cells expanded from a subject, or cells in a model system. Exemplary model systems include, without limitation, plant and animal models of a disease state.

To identify a variant molecule associated with prevention, reduction or treatment of a disease state, a variant nucleic acid library described herein is expressed in a cell associated with a disease state, or one in which a cell a disease state can be induced. In some instances, an agent is used to induce a disease state in cells. Exemplary tools for disease state induction include, without limitation, a Cre/Lox recombination system, LPS inflammation induction, and streptozotocin to induce hypoglycemia. The cells associated with a disease state may be cells from a model system or cultured cells, as well as cells from a subject having a particular disease condition. Exemplary disease conditions include a bacterial, fungal, viral, autoimmune, or proliferative disorder (e.g., cancer). In some instances, the variant nucleic acid library is expressed in the model system, cell line, or primary cells derived from a subject, and screened for changes in at least one cellular activity. Exemplary cellular activities include, without limitation, proliferation, cycle progression, cell death, adhesion, migration, reproduction, cell signaling, energy production, oxygen utilization, metabolic activity, and aging, response to free radical damage, or any combination thereof

Substrates

Devices used as a surface for polynucleotide synthesis may be in the form of substrates which include, without limitation, homogenous array surfaces, patterned array surfaces, channels, beads, gels, and the like. Provided herein are substrates comprising a plurality of clusters, wherein each cluster comprises a plurality of loci that support the attachment and synthesis of polynucleotides. In some instances, substrates comprise a homogenous array surface. For example, the homogenous array surface is a homogenous plate. The term “locus” as used herein refers to a discrete region on a structure which provides support for polynucleotides encoding for a single predetermined sequence to extend from the surface. In some instances, a locus is on a two dimensional surface, e.g., a substantially planar surface. In some instances, a locus is on a three-dimensional surface, e.g., a well, microwell, channel, or post. In some instances, a surface of a locus comprises a material that is actively functionalized to attach to at least one nucleotide for polynucleotide synthesis, or preferably, a population of identical nucleotides for synthesis of a population of polynucleotides. In some instances, polynucleotide refers to a population of polynucleotides encoding for the same nucleic acid sequence. In some cases, a surface of a substrate is inclusive of one or a plurality of surfaces of a substrate. The average error rates for polynucleotides synthesized within a library described here using the systems and methods provided are often less than 1 in 1000, less than about 1 in 2000, less than about 1 in 3000 or less often without error correction.

Provided herein are surfaces that support the parallel synthesis of a plurality of polynucleotides having different predetermined sequences at addressable locations on a common support. In some instances, a substrate provides support for the synthesis of more than 50, 100, 200, 400, 600, 800, 1000, 1200, 1400, 1600, 1800, 2,000; 5,000; 10,000; 20,000; 50,000; 100,000; 200,000; 300,000; 400,000; 500,000; 600,000; 700,000; 800,000; 900,000; 1,000,000; 1,200,000; 1,400,000; 1,600,000; 1,800,000; 2,000,000; 2,500,000; 3,000,000; 3,500,000; 4,000,000; 4,500,000; 5,000,000; 10,000,000 or more non-identical polynucleotides. In some cases, the surfaces provide support for the synthesis of more than 50, 100, 200, 400, 600, 800, 1000, 1200, 1400, 1600, 1800, 2,000; 5,000; 10,000; 20,000; 50,000; 100,000; 200,000; 300,000; 400,000; 500,000; 600,000; 700,000; 800,000; 900,000; 1,000,000; 1,200,000; 1,400,000; 1,600,000; 1,800,000; 2,000,000; 2,500,000; 3,000,000; 3,500,000; 4,000,000; 4,500,000; 5,000,000; 10,000,000 or more polynucleotides encoding for distinct sequences. In some instances, at least a portion of the polynucleotides have an identical sequence or are configured to be synthesized with an identical sequence. In some instances, the substrate provides a surface environment for the growth of polynucleotides having at least 80, 90, 100, 120, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 bases or more.

Provided herein are methods for polynucleotide synthesis on distinct loci of a substrate, wherein each locus supports the synthesis of a population of polynucleotides. In some cases, each locus supports the synthesis of a population of polynucleotides having a different sequence than a population of polynucleotides grown on another locus. In some instances, each polynucleotide sequence is synthesized with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more redundancy across different loci within the same cluster of loci on a surface for polynucleotide synthesis. In some instances, the loci of a substrate are located within a plurality of clusters. In some instances, a substrate comprises at least 10, 500, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 11000, 12000, 13000, 14000, 15000, 20000, 30000, 40000, 50000 or more clusters. In some instances, a substrate comprises more than 2,000; 5,000; 10,000; 100,000; 200,000; 300,000; 400,000; 500,000; 600,000; 700,000; 800,000; 900,000; 1,000,000; 1,100,000; 1,200,000; 1,300,000; 1,400,000; 1,500,000; 1,600,000; 1,700,000; 1,800,000; 1,900,000; 2,000,000; 300,000; 400,000; 500,000; 600,000; 700,000; 800,000; 900,000; 1,000,000; 1,200,000; 1,400,000; 1,600,000; 1,800,000; 2,000,000; 2,500,000; 3,000,000; 3,500,000; 4,000,000; 4,500,000; 5,000,000; or 10,000,000 or more distinct loci. In some instances, a substrate comprises about 10,000 distinct loci. The amount of loci within a single cluster is varied in different instances. In some cases, each cluster includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 130, 150, 200, 300, 400, 500 or more loci. In some instances, each cluster includes about 50-500 loci. In some instances, each cluster includes about 100-200 loci. In some instances, each cluster includes about 100-150 loci. In some instances, each cluster includes about 109, 121, 130 or 137 loci. In some instances, each cluster includes about 19, 20, 61, 64 or more loci. Alternatively or in combination, polynucleotide synthesis occurs on a homogenous array surface.

In some instances, the number of distinct polynucleotides synthesized on a substrate is dependent on the number of distinct loci available in the substrate. In some instances, the density of loci within a cluster or surface of a substrate is at least or about 1, 10, 25, 50, 65, 75, 100, 130, 150, 175, 200, 300, 400, 500, 1,000 or more loci per mm². In some cases, a substrate comprises 10-500, 25-400, 50-500, 100-500, 150-500, 10-250, 50-250, 10-200, or 50-200 mm². In some instances, the distance between the centers of two adjacent loci within a cluster or surface is from about 10-500, from about 10-200, or from about 10-100 um. In some instances, the distance between two centers of adjacent loci is greater than about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 um. In some instances, the distance between the centers of two adjacent loci is less than about 200, 150, 100, 80, 70, 60, 50, 40, 30, 20 or 10 um. In some instances, each locus has a width of about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 um. In some cases, each locus has a width of about 0.5-100, 0.5-50, 10-75, or 0.5-50 um.

In some instances, the density of clusters within a substrate is at least or about 1 cluster per 100 mm², 1 cluster per 10 mm², 1 cluster per 5 mm², 1 cluster per 4 mm², 1 cluster per 3 mm², 1 cluster per 2 mm², 1 cluster per 1 mm², 2 clusters per 1 mm², 3 clusters per 1 mm², 4 clusters per 1 mm², 5 clusters per 1 mm², 10 clusters per 1 mm², 50 clusters per 1 mm² or more. In some instances, a substrate comprises from about 1 cluster per 10 mm² to about 10 clusters per 1 mm². In some instances, the distance between the centers of two adjacent clusters is at least or about 50, 100, 200, 500, 1000, 2000, or 5000 um. In some cases, the distance between the centers of two adjacent clusters is between about 50-100, 50-200, 50-300, 50-500, and 100-2000 um. In some cases, the distance between the centers of two adjacent clusters is between about 0.05-50, 0.05-10, 0.05-5, 0.05-4, 0.05-3, 0.05-2, 0.1-10, 0.2-10, 0.3-10, 0.4-10, 0.5-10, 0.5-5, or 0.5-2 mm. In some cases, each cluster has a cross section of about 0.5 to about 2, about 0.5 to about 1, or about 1 to about 2 mm. In some cases, each cluster has a cross section of about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2 mm. In some cases, each cluster has an interior cross section of about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.15, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2 mm.

In some instances, a substrate is about the size of a standard 96 well plate, for example between about 100 and about 200 mm by between about 50 and about 150 mm. In some instances, a substrate has a diameter less than or equal to about 1000, 500, 450, 400, 300, 250, 200, 150, 100 or 50 mm. In some instances, the diameter of a substrate is between about 25-1000, 25-800, 25-600, 25-500, 25-400, 25-300, or 25-200 mm. In some instances, a substrate has a planar surface area of at least about 100; 200; 500; 1,000; 2,000; 5,000; 10,000; 12,000; 15,000; 20,000; 30,000; 40,000; 50,000 mm² or more. In some instances, the thickness of a substrate is between about 50-2000, 50-1000, 100-1000, 200-1000, or 250-1000 mm.

Surface Materials

Substrates, devices, and reactors provided herein are fabricated from any variety of materials suitable for the methods, compositions, and systems described herein. In certain instances, substrate materials are fabricated to exhibit a low level of nucleotide binding. In some instances, substrate materials are modified to generate distinct surfaces that exhibit a high level of nucleotide binding. In some instances, substrate materials are transparent to visible and/or UV light. In some instances, substrate materials are sufficiently conductive, e.g., are able to form uniform electric fields across all or a portion of a substrate. In some instances, conductive materials are connected to an electric ground. In some instances, the substrate is heat conductive or insulated. In some instances, the materials are chemical resistant and heat resistant to support chemical or biochemical reactions, for example polynucleotide synthesis reaction processes. In some instances, a substrate comprises flexible materials. For flexible materials, materials can include, without limitation: nylon, both modified and unmodified, nitrocellulose, polypropylene, and the like. In some instances, a substrate comprises rigid materials. For rigid materials, materials can include, without limitation: glass; fuse silica; silicon, plastics (for example polytetrafluoroethylene, polypropylene, polystyrene, polycarbonate, and blends thereof, and the like); metals (for example, gold, platinum, and the like). The substrate, solid support or reactors can be fabricated from a material selected from the group consisting of silicon, polystyrene, agarose, dextran, cellulosic polymers, polyacrylamides, polydimethylsiloxane (PDMS), and glass. The substrates/solid supports or the microstructures, reactors therein may be manufactured with a combination of materials listed herein or any other suitable material known in the art.

Surface Architecture

Provided herein are substrates for the methods, compositions, and systems described herein, wherein the substrates have a surface architecture suitable for the methods, compositions, and systems described herein. In some instances, a substrate comprises raised and/or lowered features. One benefit of having such features is an increase in surface area to support polynucleotide synthesis. In some instances, a substrate having raised and/or lowered features is referred to as a three-dimensional substrate. In some cases, a three-dimensional substrate comprises one or more channels. In some cases, one or more loci comprise a channel. In some cases, the channels are accessible to reagent deposition via a deposition device such as a material deposition device. In some cases, reagents and/or fluids collect in a larger well in fluid communication one or more channels. For example, a substrate comprises a plurality of channels corresponding to a plurality of loci with a cluster, and the plurality of channels are in fluid communication with one well of the cluster. In some methods, a library of polynucleotides is synthesized in a plurality of loci of a cluster.

Provided herein are substrates for the methods, compositions, and systems described herein, wherein the substrates are configured for polynucleotide synthesis. In some instances, the structure is configured to allow for controlled flow and mass transfer paths for polynucleotide synthesis on a surface. In some instances, the configuration of a substrate allows for the controlled and even distribution of mass transfer paths, chemical exposure times, and/or wash efficacy during polynucleotide synthesis. In some instances, the configuration of a substrate allows for increased sweep efficiency, for example by providing sufficient volume for a growing polynucleotide such that the excluded volume by the growing polynucleotide does not take up more than 50, 45, 40, 35, 30, 25, 20, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1%, or less of the initially available volume that is available or suitable for growing the polynucleotide. In some instances, a three-dimensional structure allows for managed flow of fluid to allow for the rapid exchange of chemical exposure.

Provided herein are substrates for the methods, compositions, and systems described herein, wherein the substrates comprise structures suitable for the methods, compositions, and systems described herein. In some instances, segregation is achieved by physical structure. In some instances, segregation is achieved by differential functionalization of the surface generating active and passive regions for polynucleotide synthesis. In some instances, differential functionalization is achieved by alternating the hydrophobicity across the substrate surface, thereby creating water contact angle effects that cause beading or wetting of the deposited reagents. Employing larger structures can decrease splashing and cross-contamination of distinct polynucleotide synthesis locations with reagents of the neighboring spots. In some cases, a device, such as a material deposition device, is used to deposit reagents to distinct polynucleotide synthesis locations. Substrates having three-dimensional features are configured in a manner that allows for the synthesis of a large number of polynucleotides (e.g., more than about 10,000) with a low error rate (e.g., less than about 1:500, 1:1000, 1:1500, 1:2,000, 1:3,000, 1:5,000, or 1:10,000). In some cases, a substrate comprises features with a density of about or greater than about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 400 or 500 features per mm².

A well of a substrate may have the same or different width, height, and/or volume as another well of the substrate. A channel of a substrate may have the same or different width, height, and/or volume as another channel of the substrate. In some instances, the diameter of a cluster or the diameter of a well comprising a cluster, or both, is between about 0.05-50, 0.05-10, 0.05-5, 0.05-4, 0.05-3, 0.05-2, 0.05-1, 0.05-0.5, 0.05-0.1, 0.1-10, 0.2-10, 0.3-10, 0.4-10, 0.5-10, 0.5-5, or 0.5-2 mm. In some instances, the diameter of a cluster or well or both is less than or about 5, 4, 3, 2, 1, 0.5, 0.1, 0.09, 0.08, 0.07, 0.06, or 0.05 mm. In some instances, the diameter of a cluster or well or both is between about 1.0 and 1.3 mm. In some instances, the diameter of a cluster or well, or both is about 1.150 mm. In some instances, the diameter of a cluster or well, or both is about 0.08 mm. The diameter of a cluster refers to clusters within a two-dimensional or three-dimensional substrate.

In some instances, the height of a well is from about 20-1000, 50-1000, 100-1000, 200-1000, 300-1000, 400-1000, or 500-1000 um. In some cases, the height of a well is less than about 1000, 900, 800, 700, or 600 um.

In some instances, a substrate comprises a plurality of channels corresponding to a plurality of loci within a cluster, wherein the height or depth of a channel is 5-500, 5-400, 5-300, 5-200, 5-100, 5-50, or 10-50 um. In some cases, the height of a channel is less than 100, 80, 60, 40, or 20 um.

In some instances, the diameter of a channel, locus (e.g., in a substantially planar substrate) or both channel and locus (e.g., in a three-dimensional substrate wherein a locus corresponds to a channel) is from about 1-1000, 1-500, 1-200, 1-100, 5-100, or 10-100 um, for example, about 90, 80, 70, 60, 50, 40, 30, 20 or 10 um. In some instances, the diameter of a channel, locus, or both channel and locus is less than about 100, 90, 80, 70, 60, 50, 40, 30, 20 or 10 um. In some instances, the distance between the center of two adjacent channels, loci, or channels and loci is from about 1-500, 1-200, 1-100, 5-200, 5-100, 5-50, or 5-30, for example, about 20 um.

Surface Modifications

Provided herein are methods for polynucleotide synthesis on a surface, wherein the surface comprises various surface modifications. In some instances, the surface modifications are employed for the chemical and/or physical alteration of a surface by an additive or subtractive process to change one or more chemical and/or physical properties of a substrate surface or a selected site or region of a substrate surface. For example, surface modifications include, without limitation, (1) changing the wetting properties of a surface, (2) functionalizing a surface, i.e., providing, modifying or substituting surface functional groups, (3) defunctionalizing a surface, i.e., removing surface functional groups, (4) otherwise altering the chemical composition of a surface, e.g., through etching, (5) increasing or decreasing surface roughness, (6) providing a coating on a surface, e.g., a coating that exhibits wetting properties that are different from the wetting properties of the surface, and/or (7) depositing particulates on a surface.

In some cases, the addition of a chemical layer on top of a surface (referred to as adhesion promoter) facilitates structured patterning of loci on a surface of a substrate. Exemplary surfaces for application of adhesion promotion include, without limitation, glass, silicon, silicon dioxide and silicon nitride. In some cases, the adhesion promoter is a chemical with a high surface energy. In some instances, a second chemical layer is deposited on a surface of a substrate. In some cases, the second chemical layer has a low surface energy. In some cases, surface energy of a chemical layer coated on a surface supports localization of droplets on the surface. Depending on the patterning arrangement selected, the proximity of loci and/or area of fluid contact at the loci are alterable.

In some instances, a substrate surface, or resolved loci, onto which nucleic acids or other moieties are deposited, e.g., for polynucleotide synthesis, are smooth or substantially planar (e.g., two-dimensional) or have irregularities, such as raised or lowered features (e.g., three-dimensional features). In some instances, a substrate surface is modified with one or more different layers of compounds. Such modification layers of interest include, without limitation, inorganic and organic layers such as metals, metal oxides, polymers, small organic molecules and the like.

In some instances, resolved loci of a substrate are functionalized with one or more moieties that increase and/or decrease surface energy. In some cases, a moiety is chemically inert. In some cases, a moiety is configured to support a desired chemical reaction, for example, one or more processes in a polynucleotide synthesis reaction. The surface energy, or hydrophobicity, of a surface is a factor for determining the affinity of a nucleotide to attach onto the surface. In some instances, a method for substrate functionalization comprises: (a) providing a substrate having a surface that comprises silicon dioxide; and (b) silanizing the surface using, a suitable silanizing agent described herein or otherwise known in the art, for example, an organofunctional alkoxysilane molecule. Methods and functionalizing agents are described in U.S. Pat. No. 5,474,796, which is herein incorporated by reference in its entirety.

In some instances, a substrate surface is functionalized by contact with a derivatizing composition that contains a mixture of silanes, under reaction conditions effective to couple the silanes to the substrate surface, typically via reactive hydrophilic moieties present on the substrate surface. Silanization generally covers a surface through self-assembly with organofunctional alkoxysilane molecules. A variety of siloxane functionalizing reagents can further be used as currently known in the art, e.g., for lowering or increasing surface energy. The organofunctional alkoxysilanes are classified according to their organic functions.

Polynucleotide Synthesis

Methods of the current disclosure for polynucleotide synthesis may include processes involving phosphoramidite chemistry. In some instances, polynucleotide synthesis comprises coupling a base with phosphoramidite. Polynucleotide synthesis may comprise coupling a base by deposition of phosphoramidite under coupling conditions, wherein the same base is optionally deposited with phosphoramidite more than once, i.e., double coupling. Polynucleotide synthesis may comprise capping of unreacted sites. In some instances, capping is optional. Polynucleotide synthesis may also comprise oxidation or an oxidation step or oxidation steps. Polynucleotide synthesis may comprise deblocking, detritylation, and sulfurization. In some instances, polynucleotide synthesis comprises either oxidation or sulfurization. In some instances, between one or each step during a polynucleotide synthesis reaction, the device is washed, for example, using tetrazole or acetonitrile. Time frames for any one step in a phosphoramidite synthesis method may be less than about 2 min, 1 min, 50 sec, 40 sec, 30 sec, 20 sec and 10 sec.

Polynucleotide synthesis using a phosphoramidite method may comprise a subsequent addition of a phosphoramidite building block (e.g., nucleoside phosphoramidite) to a growing polynucleotide chain for the formation of a phosphite triester linkage. Phosphoramidite polynucleotide synthesis proceeds in the 3′ to 5′ direction. Phosphoramidite polynucleotide synthesis allows for the controlled addition of one nucleotide to a growing nucleic acid chain per synthesis cycle. In some instances, each synthesis cycle comprises a coupling step. Phosphoramidite coupling involves the formation of a phosphite triester linkage between an activated nucleoside phosphoramidite and a nucleoside bound to the substrate, for example, via a linker. In some instances, the nucleoside phosphoramidite is provided to the device activated. In some instances, the nucleoside phosphoramidite is provided to the device with an activator. In some instances, nucleoside phosphoramidites are provided to the device in a 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100-fold excess or more over the substrate-bound nucleosides. In some instances, the addition of nucleoside phosphoramidite is performed in an anhydrous environment, for example, in anhydrous acetonitrile. Following addition of a nucleoside phosphoramidite, the device is optionally washed. In some instances, the coupling step is repeated one or more additional times, optionally with a wash step between nucleoside phosphoramidite additions to the substrate. In some instances, a polynucleotide synthesis method used herein comprises 1, 2, 3 or more sequential coupling steps. Prior to coupling, in many cases, the nucleoside bound to the device is de-protected by removal of a protecting group, where the protecting group functions to prevent polymerization. A common protecting group is 4,4′-dimethoxytrityl (DMT).

Following coupling, phosphoramidite polynucleotide synthesis methods optionally comprise a capping step. In a capping step, the growing polynucleotide is treated with a capping agent. A capping step is useful to block unreacted substrate-bound 5′-OH groups after coupling from further chain elongation, preventing the formation of polynucleotides with internal base deletions. Further, phosphoramidites activated with 1H-tetrazole may react, to a small extent, with the O6 position of guanosine. Without being bound by theory, upon oxidation with I₂/water, this side product, possibly via O6-N7 migration, may undergo depurination. The apurinic sites may end up being cleaved in the course of the final deprotection of the polynucleotide thus reducing the yield of the full-length product. The O6 modifications may be removed by treatment with the capping reagent prior to oxidation with I₂/water. In some instances, inclusion of a capping step during polynucleotide synthesis decreases the error rate as compared to synthesis without capping. As an example, the capping step comprises treating the substrate-bound polynucleotide with a mixture of acetic anhydride and 1-methylimidazole. Following a capping step, the device is optionally washed.

In some instances, following addition of a nucleoside phosphoramidite, and optionally after capping and one or more wash steps, the device bound growing nucleic acid is oxidized. The oxidation step comprises the phosphite triester is oxidized into a tetracoordinated phosphate triester, a protected precursor of the naturally occurring phosphate diester internucleoside linkage. In some instances, oxidation of the growing polynucleotide is achieved by treatment with iodine and water, optionally in the presence of a weak base (e.g., pyridine, lutidine, collidine). Oxidation may be carried out under anhydrous conditions using, e.g. tert-Butyl hydroperoxide or (1S)-(+)-(10-camphorsulfonyl)-oxaziridine (CSO). In some methods, a capping step is performed following oxidation. A second capping step allows for device drying, as residual water from oxidation that may persist can inhibit subsequent coupling. Following oxidation, the device and growing polynucleotide is optionally washed. In some instances, the step of oxidation is substituted with a sulfurization step to obtain polynucleotide phosphorothioates, wherein any capping steps can be performed after the sulfurization. Many reagents are capable of the efficient sulfur transfer, including but not limited to 3-(Dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-3-thione, DDTT, 3H-1,2-benzodithiol-3-one 1,1-dioxide, also known as Beaucage reagent, and N,N,N′N′-Tetraethylthiuram disulfide (TETD).

In order for a subsequent cycle of nucleoside incorporation to occur through coupling, the protected 5′ end of the device bound growing polynucleotide is removed so that the primary hydroxyl group is reactive with a next nucleoside phosphoramidite. In some instances, the protecting group is DMT and deblocking occurs with trichloroacetic acid in dichloromethane. Conducting detritylation for an extended time or with stronger than recommended solutions of acids may lead to increased depurination of solid support-bound polynucleotide and thus reduces the yield of the desired full-length product. Methods and compositions of the disclosure described herein provide for controlled deblocking conditions limiting undesired depurination reactions. In some instances, the device bound polynucleotide is washed after deblocking. In some instances, efficient washing after deblocking contributes to synthesized polynucleotides having a low error rate.

Methods for the synthesis of polynucleotides typically involve an iterating sequence of the following steps: application of a protected monomer to an actively functionalized surface (e.g., locus) to link with either the activated surface, a linker or with a previously deprotected monomer; deprotection of the applied monomer so that it is reactive with a subsequently applied protected monomer; and application of another protected monomer for linking One or more intermediate steps include oxidation or sulfurization. In some instances, one or more wash steps precede or follow one or all of the steps.

Methods for phosphoramidite-based polynucleotide synthesis comprise a series of chemical steps. In some instances, one or more steps of a synthesis method involve reagent cycling, where one or more steps of the method comprise application to the device of a reagent useful for the step. For example, reagents are cycled by a series of liquid deposition and vacuum drying steps. For substrates comprising three-dimensional features such as wells, microwells, channels and the like, reagents are optionally passed through one or more regions of the device via the wells and/or channels.

Methods and systems described herein relate to polynucleotide synthesis devices for the synthesis of polynucleotides. The synthesis may be in parallel. For example, at least or about at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 10000, 50000, 75000, 100000 or more polynucleotides can be synthesized in parallel. The total number polynucleotides that may be synthesized in parallel may be from 2-100000, 3-50000, 4-10000, 5-1000, 6-900, 7-850, 8-800, 9-750, 10-700, 11-650, 12-600, 13-550, 14-500, 15-450, 16-400, 17-350, 18-300, 19-250, 20-200, 21-150, 22-100, 23-50, 24-45, 25-40, 30-35. Those of skill in the art appreciate that the total number of polynucleotides synthesized in parallel may fall within any range bound by any of these values, for example 25-100. The total number of polynucleotides synthesized in parallel may fall within any range defined by any of the values serving as endpoints of the range. Total molar mass of polynucleotides synthesized within the device or the molar mass of each of the polynucleotides may be at least or at least about 10, 20, 30, 40, 50, 100, 250, 500, 750, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 25000, 50000, 75000, 100000 picomoles, or more. The length of each of the polynucleotides or average length of the polynucleotides within the device may be at least or about at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500 nucleotides, or more. The length of each of the polynucleotides or average length of the polynucleotides within the device may be at most or about at most 500, 400, 300, 200, 150, 100, 50, 45, 35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 nucleotides, or less. The length of each of the polynucleotides or average length of the polynucleotides within the device may fall from 10-500, 9-400, 11-300, 12-200, 13-150, 14-100, 15-50, 16-45, 17-40, 18-35, 19-25. Those of skill in the art appreciate that the length of each of the polynucleotides or average length of the polynucleotides within the device may fall within any range bound by any of these values, for example 100-300. The length of each of the polynucleotides or average length of the polynucleotides within the device may fall within any range defined by any of the values serving as endpoints of the range.

Methods for polynucleotide synthesis on a surface provided herein allow for synthesis at a fast rate. As an example, at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 125, 150, 175, 200 nucleotides per hour, or more are synthesized. Nucleotides include adenine, guanine, thymine, cytosine, uridine building blocks, or analogs/modified versions thereof. In some instances, libraries of polynucleotides are synthesized in parallel on substrate. For example, a device comprising about or at least about 100; 1,000; 10,000; 30,000; 75,000; 100,000; 1,000,000; 2,000,000; 3,000,000; 4,000,000; or 5,000,000 resolved loci is able to support the synthesis of at least the same number of distinct polynucleotides, wherein polynucleotide encoding a distinct sequence is synthesized on a resolved locus. In some instances, a library of polynucleotides is synthesized on a device with low error rates described herein in less than about three months, two months, one month, three weeks, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 days, 24 hours or less. In some instances, larger nucleic acids assembled from a polynucleotide library synthesized with low error rate using the substrates and methods described herein are prepared in less than about three months, two months, one month, three weeks, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 days, 24 hours or less.

In some instances, methods described herein provide for generation of a library of nucleic acids comprising variant nucleic acids differing at a plurality of codon sites. In some instances, a nucleic acid may have 1 site, 2 sites, 3 sites, 4 sites, 5 sites, 6 sites, 7 sites, 8 sites, 9 sites, 10 sites, 11 sites, 12 sites, 13 sites, 14 sites, 15 sites, 16 sites, 17 sites 18 sites, 19 sites, 20 sites, 30 sites, 40 sites, 50 sites, or more of variant codon sites.

In some instances, the one or more sites of variant codon sites may be adjacent. In some instances, the one or more sites of variant codon sites may not be adjacent and separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more codons.

In some instances, a nucleic acid may comprise multiple sites of variant codon sites, wherein all the variant codon sites are adjacent to one another, forming a stretch of variant codon sites. In some instances, a nucleic acid may comprise multiple sites of variant codon sites, wherein none the variant codon sites are adjacent to one another. In some instances, a nucleic acid may comprise multiple sites of variant codon sites, wherein some the variant codon sites are adjacent to one another, forming a stretch of variant codon sites, and some of the variant codon sites are not adjacent to one another.

Referring to the Figures, FIG. 2 illustrates an exemplary process workflow for synthesis of nucleic acids (e.g., genes) from shorter nucleic acids. The workflow is divided generally into phases: (1) de novo synthesis of a single stranded nucleic acid library, (2) joining nucleic acids to form larger fragments, (3) error correction, (4) quality control, and (5) shipment. Prior to de novo synthesis, an intended nucleic acid sequence or group of nucleic acid sequences is preselected. For example, a group of genes is preselected for generation.

Once large nucleic acids for generation are selected, a predetermined library of nucleic acids is designed for de novo synthesis. Various suitable methods are known for generating high density polynucleotide arrays. In the workflow example, a device surface layer is provided. In the example, chemistry of the surface is altered in order to improve the polynucleotide synthesis process. Areas of low surface energy are generated to repel liquid while areas of high surface energy are generated to attract liquids. The surface itself may be in the form of a planar surface or contain variations in shape, such as protrusions or microwells which increase surface area. In the workflow example, high surface energy molecules selected serve a dual function of supporting DNA chemistry, as disclosed in International Patent Application Publication WO/2015/021080, which is herein incorporated by reference in its entirety.

In situ preparation of polynucleotide arrays is generated on a solid support and utilizes single nucleotide extension process to extend multiple oligomers in parallel. A deposition device, such as a material deposition device 201, is designed to release reagents in a step wise fashion such that multiple polynucleotides extend, in parallel, one residue at a time to generate oligomers with a predetermined nucleic acid sequence 202. In some instances, polynucleotides are cleaved from the surface at this stage. Cleavage includes gas cleavage, e.g., with ammonia or methylamine.

The generated polynucleotide libraries are placed in a reaction chamber. In this exemplary workflow, the reaction chamber (also referred to as “nanoreactor”) is a silicon coated well, containing PCR reagents and lowered onto the polynucleotide library 203. Prior to or after the sealing 204 of the polynucleotides, a reagent is added to release the polynucleotides from the substrate. In the exemplary workflow, the polynucleotides are released subsequent to sealing of the nanoreactor 205. Once released, fragments of single stranded polynucleotides hybridize in order to span an entire long range sequence of DNA. Partial hybridization 205 is possible because each synthesized polynucleotide is designed to have a small portion overlapping with at least one other polynucleotide in the pool.

After hybridization, a PCA reaction is commenced. During the polymerase cycles, the polynucleotides anneal to complementary fragments and gaps are filled in by a polymerase. Each cycle increases the length of various fragments randomly depending on which polynucleotides find each other. Complementarity amongst the fragments allows for forming a complete large span of double stranded DNA 206.

After PCA is complete, the nanoreactor is separated from the device 207 and positioned for interaction with a device having primers for PCR 208. After sealing, the nanoreactor is subject to PCR 209 and the larger nucleic acids are amplified. After PCR 210, the nanochamber is opened 211, error correction reagents are added 212, the chamber is sealed 213 and an error correction reaction occurs to remove mismatched base pairs and/or strands with poor complementarity from the double stranded PCR amplification products 214. The nanoreactor is opened and separated 215. Error corrected product is next subject to additional processing steps, such as PCR and molecular bar coding, and then packaged 222 for shipment 223.

In some instances, quality control measures are taken. After error correction, quality control steps include for example interaction with a wafer having sequencing primers for amplification of the error corrected product 216, sealing the wafer to a chamber containing error corrected amplification product 217, and performing an additional round of amplification 218. The nanoreactor is opened 219 and the products are pooled 220 and sequenced 221. After an acceptable quality control determination is made, the packaged product 222 is approved for shipment 223.

In some instances, a nucleic acid generate by a workflow such as that in FIG. 2 is subject to mutagenesis using overlapping primers disclosed herein. In some instances, a library of primers are generated by in situ preparation on a solid support and utilize single nucleotide extension process to extend multiple oligomers in parallel. A deposition device, such as a material deposition device, is designed to release reagents in a step wise fashion such that multiple polynucleotides extend, in parallel, one residue at a time to generate oligomers with a predetermined nucleic acid sequence 202.

Computer Systems

Any of the systems described herein, may be operably linked to a computer and may be automated through a computer either locally or remotely. In various instances, the methods and systems of the disclosure may further comprise software programs on computer systems and use thereof. Accordingly, computerized control for the synchronization of the dispense/vacuum/refill functions such as orchestrating and synchronizing the material deposition device movement, dispense action and vacuum actuation are within the bounds of the disclosure. The computer systems may be programmed to interface between the user specified base sequence and the position of a material deposition device to deliver the correct reagents to specified regions of the substrate.

The computer system 300 illustrated in FIG. 3 may be understood as a logical apparatus that can read instructions from media 311 and/or a network port 305, which can optionally be connected to server 309 having fixed media 312. The system, such as shown in FIG. 3 can include a CPU 301, disk drives 303, optional input devices such as keyboard 315 and/or mouse 316 and optional monitor 307. Data communication can be achieved through the indicated communication medium to a server at a local or a remote location. The communication medium can include any means of transmitting and/or receiving data. For example, the communication medium can be a network connection, a wireless connection or an internet connection. Such a connection can provide for communication over the World Wide Web. It is envisioned that data relating to the present disclosure can be transmitted over such networks or connections for reception and/or review by a party 322 as illustrated in FIG. 3.

FIG. 4 is a block diagram illustrating a first example architecture of a computer system 400 that can be used in connection with example instances of the present disclosure. As depicted in FIG. 4, the example computer system can include a processor 402 for processing instructions. Non-limiting examples of processors include: Intel Xeon™ processor, AMD Opteron™ processor, Samsung 32-bit RISC ARM 1176JZ(F)-S v1.0™ processor, ARM Cortex-A8 Samsung S5PC100™ processor, ARM Cortex-A8 Apple A4™ processor, Marvell PXA 930™ processor, or a functionally-equivalent processor. Multiple threads of execution can be used for parallel processing. In some instances, multiple processors or processors with multiple cores can also be used, whether in a single computer system, in a cluster, or distributed across systems over a network comprising a plurality of computers, cell phones, and/or personal data assistant devices.

As illustrated in FIG. 4, a high speed cache 404 can be connected to, or incorporated in, the processor 402 to provide a high speed memory for instructions or data that have been recently, or are frequently, used by processor 402. The processor 402 is connected to a north bridge 406 by a processor bus 408. The north bridge 406 is connected to random access memory (RAM) 410 by a memory bus 412 and manages access to the RAM 410 by the processor 402. The north bridge 406 is also connected to a south bridge 414 by a chipset bus 416. The south bridge 414 is, in turn, connected to a peripheral bus 418. The peripheral bus can be, for example, PCI, PCI-X, PCI Express, or other peripheral bus. The north bridge and south bridge are often referred to as a processor chipset and manage data transfer between the processor, RAM, and peripheral components on the peripheral bus 418. In some alternative architectures, the functionality of the north bridge can be incorporated into the processor instead of using a separate north bridge chip. In some instances, system 400 can include an accelerator card 422 attached to the peripheral bus 418. The accelerator can include field programmable gate arrays (FPGAs) or other hardware for accelerating certain processing. For example, an accelerator can be used for adaptive data restructuring or to evaluate algebraic expressions used in extended set processing.

Software and data are stored in external storage 424 and can be loaded into RAM 410 and/or cache 404 for use by the processor. The system 400 includes an operating system for managing system resources; non-limiting examples of operating systems include: Linux, Windows™, MACOS™, BlackBerry OS™, iOS™, and other functionally-equivalent operating systems, as well as application software running on top of the operating system for managing data storage and optimization in accordance with example instances of the present disclosure. In this example, system 400 also includes network interface cards (NICs) 420 and 421 connected to the peripheral bus for providing network interfaces to external storage, such as Network Attached Storage (NAS) and other computer systems that can be used for distributed parallel processing.

FIG. 5 is a diagram showing a network 500 with a plurality of computer systems 502 a, and 502 b, a plurality of cell phones and personal data assistants 502 c, and Network Attached Storage (NAS) 504 a, and 504 b. In example instances, systems 502 a, 502 b, and 502 c can manage data storage and optimize data access for data stored in Network Attached Storage (NAS) 504 a and 504 b. A mathematical model can be used for the data and be evaluated using distributed parallel processing across computer systems 502 a, and 502 b, and cell phone and personal data assistant systems 502 c. Computer systems 502 a, and 502 b, and cell phone and personal data assistant systems 502 c can also provide parallel processing for adaptive data restructuring of the data stored in Network Attached Storage (NAS) 504 a and 504 b. FIG. 5 illustrates an example only, and a wide variety of other computer architectures and systems can be used in conjunction with the various instances of the present disclosure. For example, a blade server can be used to provide parallel processing. Processor blades can be connected through a back plane to provide parallel processing. Storage can also be connected to the back plane or as Network Attached Storage (NAS) through a separate network interface. In some example instances, processors can maintain separate memory spaces and transmit data through network interfaces, back plane or other connectors for parallel processing by other processors. In other instances, some or all of the processors can use a shared virtual address memory space.

FIG. 6 is a block diagram of a multiprocessor computer system using a shared virtual address memory space in accordance with an example instance. The system includes a plurality of processors 602 a-f that can access a shared memory subsystem 604. The system incorporates a plurality of programmable hardware memory algorithm processors (MAPs) 606 a-f in the memory subsystem 604. Each MAP 606 a-f can comprise a memory 608 a-f and one or more field programmable gate arrays (FPGAs) 610 a-f. The MAP provides a configurable functional unit and particular algorithms or portions of algorithms can be provided to the FPGAs 610 a-f for processing in close coordination with a respective processor. For example, the MAPs can be used to evaluate algebraic expressions regarding the data model and to perform adaptive data restructuring in example instances. In this example, each MAP is globally accessible by all of the processors for these purposes. In one configuration, each MAP can use Direct Memory Access (DMA) to access an associated memory 608 a-f, allowing it to execute tasks independently of, and asynchronously from the respective microprocessor 602 a-f. In this configuration, a MAP can feed results directly to another MAP for pipelining and parallel execution of algorithms.

The above computer architectures and systems are examples only, and a wide variety of other computer, cell phone, and personal data assistant architectures and systems can be used in connection with example instances, including systems using any combination of general processors, co-processors, FPGAs and other programmable logic devices, system on chips (SOCs), application specific integrated circuits (ASICs), and other processing and logic elements. In some instances, all or part of the computer system can be implemented in software or hardware. Any variety of data storage media can be used in connection with example instances, including random access memory, hard drives, flash memory, tape drives, disk arrays, Network Attached Storage (NAS) and other local or distributed data storage devices and systems.

In example instances, the computer system can be implemented using software modules executing on any of the above or other computer architectures and systems. In other instances, the functions of the system can be implemented partially or completely in firmware, programmable logic devices such as field programmable gate arrays (FPGAs) as referenced in FIG. 4, system on chips (SOCs), application specific integrated circuits (ASICs), or other processing and logic elements. For example, the Set Processor and Optimizer can be implemented with hardware acceleration through the use of a hardware accelerator card, such as accelerator card 422 illustrated in FIG. 4.

The following examples are set forth to illustrate more clearly the principle and practice of embodiments disclosed herein to those skilled in the art and are not to be construed as limiting the scope of any claimed embodiments. Unless otherwise stated, all parts and percentages are on a weight basis.

EXAMPLES

The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.

Example 1: Functionalization of a Device Surface

A device was functionalized to support the attachment and synthesis of a library of polynucleotides. The device surface was first wet cleaned using a piranha solution comprising 90% H₂SO₄ and 10% H₂O₂ for 20 minutes. The device was rinsed in several beakers with DI water, held under a DI water gooseneck faucet for 5 min, and dried with N₂. The device was subsequently soaked in NH₄OH (1:100; 3 mL:300 mL) for 5 min, rinsed with DI water using a handgun, soaked in three successive beakers with DI water for 1 min each, and then rinsed again with DI water using the handgun. The device was then plasma cleaned by exposing the device surface to O₂. A SAMCO PC-300 instrument was used to plasma etch O₂ at 250 watts for 1 min in downstream mode.

The cleaned device surface was actively functionalized with a solution comprising N-(3-triethoxysilylpropyl)-4-hydroxybutyramide using a YES-1224P vapor deposition oven system with the following parameters: 0.5 to 1 ton, 60 min, 70° C., 135° C. vaporizer. The device surface was resist coated using a Brewer Science 200× spin coater. SPR™ 3612 photoresist was spin coated on the device at 2500 rpm for 40 sec. The device was pre-baked for 30 min at 90° C. on a Brewer hot plate. The device was subjected to photolithography using a Karl Suss MA6 mask aligner instrument. The device was exposed for 2.2 sec and developed for 1 min in MSF 26A. Remaining developer was rinsed with the handgun and the device soaked in water for 5 min. The device was baked for 30 min at 100° C. in the oven, followed by visual inspection for lithography defects using a Nikon L200. A descum process was used to remove residual resist using the SAMCO PC-300 instrument to O₂ plasma etch at 250 watts for 1 min.

The device surface was passively functionalized with a 100 μL solution of perfluorooctyltrichlorosilane mixed with 10 μL light mineral oil. The device was placed in a chamber, pumped for 10 min, and then the valve was closed to the pump and left to stand for 10 min. The chamber was vented to air. The device was resist stripped by performing two soaks for 5 min in 500 mL NMP at 70° C. with ultrasonication at maximum power (9 on Crest system). The device was then soaked for 5 min in 500 mL isopropanol at room temperature with ultrasonication at maximum power. The device was dipped in 300 mL of 200 proof ethanol and blown dry with N₂. The functionalized surface was activated to serve as a support for polynucleotide synthesis.

Example 2: Synthesis of a 50-Mer Sequence on an Oligonucleotide Synthesis Device

A two dimensional oligonucleotide synthesis device was assembled into a flowcell, which was connected to a flowcell (Applied Biosystems (ABI394 DNA Synthesizer”). The two-dimensional oligonucleotide synthesis device was uniformly functionalized with N-(3-TRIETHOXYSILYLPROPYL)-4-HYDROXYBUTYRAMIDE (Gelest) was used to synthesize an exemplary polynucleotide of 50 bp (“50-mer polynucleotide”) using polynucleotide synthesis methods described herein.

The sequence of the 50-mer was as described.

5′AGACAATCAACCATTTGGGGTGGACAGCCTTGACCTCTAGACTTCGG CAT##TTTTTTTTTT3′, where # denotes Thymidine-succinyl hexamide CED phosphoramidite (CLP-2244 from ChemGenes), which is a cleavable linker enabling the release of oligos from the surface during deprotection.

The synthesis was done using standard DNA synthesis chemistry (coupling, capping, oxidation, and deblocking) according to the protocol in Table 2 and an ABI synthesizer.

TABLE 2 Synthesis protocols General DNA Table 2 Synthesis Time Process Name Process Step (sec) WASH (Acetonitrile Acetonitrile 4 Wash Flow) System Flush Acetonitrile 23 to Flowcell N2 System Flush 4 Acetonitrile 4 System Flush DNA BASE ADDITION Activator 2 (Phosphoramidite + Manifold Flush Activator Flow) Activator to 6 Flowcell Activator + 6 Phosphoramidite to Flowcell Activator to 0.5 Flowcell Activator + 5 Phosphoramidite to Flowcell Activator to 0.5 Flowcell Activator + 5 Phosphoramidite to Flowcell Activator to 0.5 Flowcell Activator + 5 Phosphoramidite to Flowcell Incubate for 25 25 sec WASH (Acetonitrile Acetonitrile 4 Wash Flow) System Flush Acetonitrile to 15 Flowcell N2 System Flush 4 Acetonitrile 4 System Flush DNA BASE ADDITION Activator 2 (Phosphoramidite + Manifold Flush Activator Flow) Activator to 5 Flowcell Activator + 18 Phosphoramidite to Flowcell Incubate for 25 25 sec WASH (Acetonitrile Acetonitrile 4 Wash Flow) System Flush Acetonitrile to 15 Flowcell N2 System Flush 4 Acetonitrile 4 System Flush CAPPING (CapA + B, CapA + B to 15 1:1, Flow) Flowcell WASH (Acetonitrile Acetonitrile 4 Wash Flow) System Flush Acetonitrile to 15 Flowcell Acetonitrile 4 System Flush OXIDATION (Oxidizer Oxidizer to 18 Flow) Flowcell WASH (Acetonitrile Acetonitrile 4 Wash Flow) System Flush N2 System Flush 4 Acetonitrile 4 System Flush Acetonitrile to 15 Flowcell Acetonitrile 4 System Flush Acetonitrile to 15 Flowcell N2 System Flush 4 Acetonitrile 4 System Flush Acetonitrile to 23 Flowcell N2 System Flush 4 Acetonitrile 4 System Flush DEBLOCKING (Deblock Deblock to 36 Flow) Flowcell WASH (Acetonitrile Acetonitrile 4 Wash Flow) System Flush N2 System Flush 4 Acetonitrile 4 System Flush Acetonitrile to 18 Flowcell N2 System Flush 4.13 Acetonitrile 4.13 System Flush Acetonitrile to 15 Flowcell

The phosphoramidite/activator combination was delivered similar to the delivery of bulk reagents through the flowcell. No drying steps were performed as the environment stays “wet” with reagent the entire time.

The flow restrictor was removed from the ABI 394 synthesizer to enable faster flow. Without flow restrictor, flow rates for amidites (0.1M in ACN), Activator, (0.25M Benzoylthiotetrazole (“BTT”; 30-3070-xx from GlenResearch) in ACN), and Ox (0.02M 12 in 20% pyridine, 10% water, and 70% THF) were roughly ˜100 uL/sec, for acetonitrile (“ACN”) and capping reagents (1:1 mix of CapA and CapB, wherein CapA is acetic anhydride in THF/Pyridine and CapB is 16% 1-methylimidizole in THF), roughly ˜200 uL/sec, and for Deblock (3% dichloroacetic acid in toluene), roughly ˜300 uL/sec (compared to ˜50 uL/sec for all reagents with flow restrictor). The time to completely push out Oxidizer was observed, the timing for chemical flow times was adjusted accordingly and an extra ACN wash was introduced between different chemicals. After polynucleotide synthesis, the chip was deprotected in gaseous ammonia overnight at 75 psi. Five drops of water were applied to the surface to recover polynucleotides. The recovered polynucleotides were then analyzed on a BioAnalyzer small RNA chip.

Example 3: Synthesis of a 100-Mer Sequence on an Oligonucleotide Synthesis Device

The same process as described in Example 2 for the synthesis of the 50-mer sequence was used for the synthesis of a 100-mer polynucleotide (“100-mer polynucleotide”; 5′ CGGGATCCTTATCGTCATCGTCGTACAGATCCCGACCCATTTGCTGTCCACCAGTCATGCTAGC CATACCATGATGATGATGATGATGAGAACCCCGCAT##TTTTTTTTTT3′, where # denotes Thymidine-succinyl hexamide CED phosphoramidite (CLP-2244 from ChemGenes) on two different silicon chips, the first one uniformly functionalized with N-(3-TRIETHOXYSILYLPROPYL)-4-HYDROXYBUTYRAMIDE and the second one functionalized with 5/95 mix of 11-acetoxyundecyltriethoxysilane and n-decyltriethoxysilane, and the polynucleotides extracted from the surface were analyzed on a BioAnalyzer instrument.

All ten samples from the two chips were further PCR amplified using a forward (5′ATGCGGGGTTCTCATCATC3′) and a reverse (5′CGGGATCCTTATCGTCATCG3′) primer in a 50 uL PCR mix (25 uL NEB Q5 mastermix, 2.5 uL 10 uM Forward primer, 2.5 uL 10 uM Reverse primer, 1 uL polynucleotide extracted from the surface, and water up to 50 uL) using the following thermalcycling program:

98° C., 30 sec

98° C., 10 sec; 63° C., 10 sec; 72° C., 10 sec; repeat 12 cycles

72° C., 2 min

The PCR products were also run on a BioAnalyzer, demonstrating sharp peaks at the 100-mer position. Next, the PCR amplified samples were cloned, and Sanger sequenced. Table 3 summarizes the results from the Sanger sequencing for samples taken from spots 1-5 from chip 1 and for samples taken from spots 6-10 from chip 2.

TABLE 3 Sequencing results Spot Error rate Cycle efficiency 1 1/763 bp 99.87% 2 1/824 bp 99.88% 3 1/780 bp 99.87% 4 1/429 bp 99.77% 5 1/1525 bp 99.93% 6 1/1615 bp 99.94% 7 1/531 bp 99.81% 8 1/1769 bp 99.94% 9 1/854 bp 99.88% 10 1/1451 bp 99.93%

Thus, the high quality and uniformity of the synthesized polynucleotides were repeated on two chips with different surface chemistries. Overall, 89% of the 100-mers that were sequenced were perfect sequences with no errors, corresponding to 233 out of 262.

Table 4 summarizes error characteristics for the sequences obtained from the polynucleotides samples from spots 1-10.

TABLE 4 Error characteristics Sample ID/ Spot no. OSA_0046/1 OSA_0047/2 OSA_0048/3 OSA_0049/4 OSA_0050/5 OSA_0051/6 Total Sequences 32 32 32 32 32 32 Sequencing Quality 25 of 28 27 of 27 26 of 30 21 of 23 25 of 26 29 of 30 Oligo Quality 23 of 25 25 of 27 22 of 26 18 of 21 24 of 25 25 of 29 ROI Match Count 2500 2698 2561 2122 2499 2666 ROI Mutation 2 2 1 3 1 0 ROI Multi Base 0 0 0 0 0 0 Deletion ROI Small Insertion 1 0 0 0 0 0 ROI Single Base 0 0 0 0 0 0 Deletion Large Deletion 0 0 1 0 0 1 Count Mutation: G > A 2 2 1 2 1 0 Mutation: T > C 0 0 0 1 0 0 ROI Error Count 3 2 2 3 1 1 ROI Error Rate Err: ~1 Err: ~1 Err: ~1 Err: ~1 Err: ~1 Err: ~1 in 834 in 1350 in 1282 in 708 in 2500 in 2667 ROI Minus Primer MP Err: ~1 MP Err: ~1 MP Err: ~1 MP Err: ~1 MP Err: ~1 MP Err: ~1 Error Rate in 763 in 824 in 780 in 429 in 1525 in 1615 Sample ID/ Spot no. OSA_0052/7 OSA_0053/8 OSA_0054/9 OSA_0055/10 Total Sequences 32 32 32 32 Sequencing Quality 27 of 31 29 of 31 28 of 29 25 of 28 Oligo Quality 22 of 27 28 of 29 26 of 28 20 of 25 ROI Match Count 2625 2899 2798 2348 ROI Mutation 2 1 2 1 ROI Multi Base 0 0 0 0 Deletion ROI Small Insertion 0 0 0 0 ROI Single Base 0 0 0 0 Deletion Large Deletion 1 0 0 0 Count Mutation: G > A 2 1 2 1 Mutation: T > C 0 0 0 0 ROI Error Count 3 1 2 1 ROI Error Rate Err: ~1 Err: ~1 Err: ~1 Err: ~1 in 876 in 2900 in 1400 in 2349 ROI Minus Primer MP Err: ~1 MP Err: ~1 MP Err: ~1 MP Err: ~1 Error Rate in 531 in 1769 in 854 in 1451

Example 4: Panning and Screening for Identification of Antibodies for SARS-CoV-2 and ACE2

This example describes identification of antibodies for SARS-CoV-2 and ACE2.

Phage displayed scFv, VHH, and Fab libraries were panned for binding to biotinylated SARS-CoV-2 S1 and human ACE2. FIG. 7 shows a schema of the panning strategy. Biotinylated antigen was bound to streptavidin coated magnetic beads at a density of 100 pmol antigen per mg of beads (Thermo Fisher #11206D). Phage libraries were blocked with 5% BSA in PBS. Following magnetic bead depletion for 1 hour at room temperature (RT), the beads were removed, and phage supernatant was transferred to 1 mg of antigen-bound beads in 1 ml PBS and incubated at RT with rotation for 1 hour. Non-binding clones were washed away by addition of 1 ml PBST, increasing the number of washes with each panning round. Trypsin was used to elute the phage bound to the antigen-bead complex. Phage were amplified in TG1 E. coli for the next round of selection. This selection strategy was repeated for four rounds, with successively lower amounts of antigen per round. Following all four selection rounds, 400 clones from each of round 2, 3, and 4 were selected for phage expression and phage ELISA screening. Data from the panning is seen in Table 5.

TABLE 5 Panning Data Antibody Titer Round 1 Round 2 Round 3 Round 4 Round 5 1 Input titer 1.5 × 10¹² 1.2 × 10¹³ 4.4 × 10¹³ 1.8 × 10¹³ — Output titer 1.2 × 10⁶  1.5 × 10⁶  2.0 × 10⁶  1.4 × 10⁸  — 2 Input titer 1.4 × 10¹² 2.6 × 10¹³ 3.0 × 10¹³ 1.0 × 10¹³ — Output titer 9.5 × 10⁵  1.2 × 10⁶  2.2 × 10⁶  1.2 × 10⁸  — 3 Input titer 1.7 × 10¹² 2.0 × 10¹³ 2.8 × 10¹³ 3.2 × 10¹³ — Output titer 1.5 × 10⁵  1.7 × 10⁶  1.5 × 10⁶  1.1 × 10⁸  — 4 Input titer 1.2 × 10¹² 1.6 × 10¹³ 3.6 × 10¹³ 1.5 × 10¹³ — Output titer 1.3 × 10⁵  2.2 × 10⁷  2.6 × 10⁷  2.5 × 10⁸  —

To test for binding to SARS-CoV-2 S1 and ACE2, phage were expressed from each picked colony by KO7 superinfection in 384 well microtiter plates. Phage containing supernatant was blocked by 1:1 addition of 4% non-fat milk (NFM). Assay plates were prepared by passive immobilization of 0.4 μg antigen in 384-well Maxisorp plates (Thermo Fisher #464718) and then blocked with 4% NFM. Following 3× wash in PBST, blocked phage supernatant was incubated for 1 hour at RT. After 3× wash in PBST, 0.3 μg/ml anti-M13-HRP (Sino Biological #11973-MM05T-H) was aliquoted for 1 hour incubation at room temperature. Binding of phage-displayed antibody was determined by absorbance at 450 nm with 3,3′,5,5′-tetramethylbenzidine (Thermo Fisher #34029). Phage that bound to antigen with 3× over background of human Fc protein were identified as potential binders for sequencing analysis. DNA was amplified by rolling circle amplification from glycerol stocks of each clone and submitted for Sanger sequencing (Genewiz) to capture the VH and VL domains. FIGS. 8A-8D shows phage ELISA data from round 4 of SARS-CoV-2 S1 (subunit 1) protein panning for antibody 1 (FIGS. 8A-8B) and antibody 2 (FIGS. 8C-8D). FIGS. 9A-9D shows phage ELISA data from round 4 of ACE2 protein panning for antibody 3 (FIGS. 9A-9B) and antibody 4 (FIGS. 9C-9D).

SARS-CoV-2 variants were tested for specificity using a phage ELISA as described above. The antigens used included Acro COVID S1 (S1N-C82E8), COVID S1 RBD Fc fusion (Antigen 1), and COVID S1 RBM Fc fusion (Antigen 2). Data from the phage ELISA is seen in Table 6A. Table 6A shows screening ELISA mean, fold over background (column A), specificity ELISA, fold over background (column B), and specificity ELISA, percent binding relative to binding to Acro S1 (column C). As seen in Table 6A, nearly all receptor binding domain (RBD) specific clones show good binding to full length subunit 1 (S1) and produced S1 RBD Fc. None of the S1 RBD variants were found to bind to S1 RBM Fc.

TABLE 6A SARS-CoV-2 Phage ELISA Column A Column B Column C ELISA S1- S1- S1- S1- Variant (Avg) Aero S1 RBD-Fc S1-Fc RBM-Fc RBD-Fc S1-Fc RBM-Fc 1-21 47.6 19.5 14.8 1.4 1.4 75.7% 7.2% 7.0% 1-22 40.6 32.7 26.5 2.5 1.5 81.2% 7.6% 4.7% 1-30 29.5 16.8 1.7 5.6 1.4 9.8% 33.3% 8.5% 1-35 28.6 21.6 1.8 1.4 1.6 8.2% 6.5% 7.3% 1-17 27.4 25.1 20.1 1.6 1.3 79.8% 6.2% 5.2% 1-27 27.2 1.5 1.9 1.3 1.6 124.5% 84.8% 108.8% 1-37 27.0 11.6 2.0 5.4 1.4 17.7% 46.7% 12.3% 1-12 25.7 1.7 1.7 1.3 1.7 104.0% 79.6% 102.5% 1-2  24.2 1.8 1.9 1.7 1.7 103.3% 95.4% 93.5% 1-3  23.9 1.6 1.8 1.5 1.5 109.3% 91.2% 91.9% 1-23 23.1 5.1 3.6 1.6 1.6 70.9% 31.1% 32.0% 1-7  22.5 6.8 3.3 1.7 1.6 48.7% 24.8% 23.0% 1-31 20.7 30.4 1.3 15.7 1.2 4.3% 51.6% 3.8% 1-4  20.6 1.0 1.4 0.9 1.1 137.5% 90.8% 105.3% 1-38 20.2 1.1 1.5 0.9 1.2 127.9% 82.8% 100.9% 1-8  19.3 12.0 11.2 1.1 1.2 92.9% 8.8% 10.3% 1-9  18.5 10.7 9.8 0.9 1.0 91.1% 8.7% 9.3% 1-32 17.9 11.5 1.5 4.0 1.1 13.1% 35.3% 9.5% 1-33 17.6 7.1 1.5 3.0 1.0 21.1% 42.1% 14.6% 1-24 32.9 12.9 11.0 1.1 1.3 85.4% 8.9% 10.3% 1-39 24.4 18.6 11.6 2.5 1.3 62.5% 13.2% 6.7% 1-40 22.9 18.7 14.3 1.3 1.1 76.7% 7.1% 6.0% 1-5  20.6 1.5 1.6 1.2 1.4 107.8% 82.9% 92.0% 1-41 18.1 4.5 2.7 1.3 1.2 58.8% 28.9% 26.3% 1-28 17.7 1.0 1.1 1.1 1.2 112.9% 109.7% 124.1% 1-10 16.9 17.4 17.4 1.3 1.1 100.5% 7.3% 6.2% 2-1  45.3 39.3 36.8 20.2 1.5 93.7% 51.3% 3.9% 2-10 43.8 38.9 39.9 9.4 1.2 102.7% 24.1% 3.1% 2-5  30.8 38.3 35.9 24.3 1.1 93.7% 63.3% 3.0% 2-2  23.4 39.4 39.6 4.7 1.1 100.4% 12.0% 2.8% 3-10 17.4 1.2 1.2 1.2 1.1 97.2% 99.6% 93.3% 1-26 19.5 1.4 1.1 1.3 1.0 76.8% 98.0% 74.7% 1-42 34.5 22.7 20.8 1.4 1.0 91.4% 6.4% 4.2% 1-13 28.2 4.8 4.3 0.9 1.2 89.3% 18.4% 24.2% 1-43 21.9 6.7 5.8 3.9 1.0 87.3% 58.3% 14.5% 1-44 24.6 10.4 8.2 1.0 0.8 78.6% 9.6% 7.6% 1-14 21.7 16.8 13.5 1.1 0.9 80.6% 6.7% 5.4% 1-6  20.8 1.8 1.3 1.1 0.8 69.6% 60.5% 45.4% 1-45 24.0 12.1 10.3 1.2 1.0 85.3% 9.6% 8.3% 1-46 21.7 4.6 3.1 1.1 0.9 66.6% 24.5% 19.8% 1-20 26.0 5.7 3.9 1.0 0.8 67.3% 17.0% 14.5% 1-47 22.6 8.1 5.5 1.2 0.9 68.9% 14.6% 11.1% 1-29 23.8 1.1 0.9 1.0 0.9 81.4% 94.0% 78.3% 1-1  32.5 4.5 4.0 1.6 1.1 90.7% 35.3% 24.5% 1-19 22.3 24.2 23.9 1.5 1.2 98.7% 6.4% 4.9% 1-16 22.1 3.4 3.1 1.0 0.9 89.7% 29.5% 27.3% 1-34 28.7 7.5 3.1 1.8 1.0 41.3% 24.5% 13.3% 1-48 22.6 2.5 2.1 0.8 0.8 84.7% 31.5% 30.3% 1-49 27.6 1.0 1.0 0.8 0.8 99.3% 85.6% 78.8% 1-18 22.7 9.8 7.0 1.1 0.8 71.0% 11.0% 8.0% 1-11 33.2 4.8 4.8 0.9 1.0 99.5% 18.7% 20.6% 1-50 21.1 13.9 12.4 1.2 0.8 88.9% 8.8% 5.9% 1-25 27.9 3.6 2.7 1.0 0.8 75.4% 28.1% 22.3% 1-36 23.6 10.1 1.2 1.1 0.8 11.5% 10.6% 8.4% 1-15 24.8 2.5 1.4 1.0 0.8 55.4% 41.5% 32.1% 2-4  15.5 37.7 38.8 7.2 1.2 102.7% 19.0% 3.1% 2-6  22.1 11.1 12.8 1.8 1.1 115.8% 16.4% 9.5% 2-11 28.1 1.1 1.0 1.2 0.9 86.3% 103.4% 76.1% 2-12 18.2 39.8 40.3 14.7 1.1 101.3% 37.0% 2.9% 2-13 19.1 27.3 32.1 3.7 0.9 117.5% 13.4% 3.1% 2-14 17.2 31.7 32.9 4.2 0.9 103.9% 13.3% 2.8% 2-7  25.3 37.2 37.3 7.7 0.9 100.3% 20.6% 2.4% 2-8  32.4 35.9 36.5 5.4 1.1 101.8% 15.0% 3.1% 2-15 13.7 31.0 28.1 3.8 0.9 90.6% 12.4% 3.0% 2-9  14.1 24.1 24.3 3.0 0.8 100.7% 12.2% 3.5%

Tables 6B-6C show Carterra SPR kinetics for SARS-CoV-2 variant antibodies ranked by off-rate (Table 6B) and by K_(D) (Table 6C). Tables 6D-6E show Carterra SPR kinetics for ACE2 variant antibodies ranked by off-rate (Table 6D) and by K_(D) (Table 6E). FIG. 10 shows that ACE2 binds to S1-RBD-Fc and S1-Fc variants.

TABLE 6B SARS-CoV-2 Carterra SPR Kinetics Ranked by Off-Rate S1- S1- ka IgG Acro S1 RBD-Fc S1-Fc RBM-Fc (M-1 s-1) Kd (s-1) 2-10 38.9 39.9 9.4 1.2 2.08E+05 1.15E−04 2-5  38.3 35.9 24.3 1.1 9.39E+04 2.59E−04 1-31 30.4 1.3 15.7 1.2 2.05E+04 7.62E−04 2-2  39.4 39.6 4.7 1.1 7.74E+04 9.06E−04 1-13 4.8 4.3 0.9 1.2 2.17E+05 1.38E−03 1-30 16.8 1.7 5.6 1.4 4.39E+04 1.64E−03 1-29 1.1 0.9 1.0 0.9 5.35E+02 1.97E−03 1-27 1.5 1.9 1.3 1.6 2.27E+05 2.85E−03 1-35 21.6 1.8 1.4 1.6 5.90E+04 5.43E−03 1-36 10.1 1.2 1.1 0.8 1.14E+05 7.85E−03 1-67 18.6 11.6 2.5 1.3 7.36E+04 8.86E−03 1-2  1.8 1.9 1.7 1.7 1.58E+03 2.72E−02 1-5  1.5 1.6 1.2 1.4 2.15E+03 5.40E−02 1-68 6.7 5.8 3.9 1.0 2.46E+06 8.75E−02 1-69 1.1 1.5 0.9 1.2 3.08E+05 1.23E−01 1-4  1.0 1.4 0.9 1.1 4.20E+04 1.24E−01 1-12 1.7 1.7 1.3 1.7 3.59E+05 1.34E−01 1-11 4.8 4.8 0.9 1.0 5.92E+05 1.43E−01 1-10 17.4 17.4 1.3 1.1 1.04E+06 1.47E−01 1-7  4.5 2.7 1.3 1.2 2.09E+05 1.55E−01 1-15 2.5 1.4 1.0 0.8 4.49E+05 1.56E−01 1-25 3.6 2.7 1.0 0.8 1.98E+06 1.56E−01 1-23 5.1 3.6 1.6 1.6 5.06E+05 1.59E−01 1-7  6.8 3.3 1.7 1.6 1.34E+06 1.70E−01 1-47 8.1 5.5 1.2 0.9 6.32E+03 2.40E−01 1-3  1.6 1.8 1.5 1.5 1.42E+06 3.04E−01 1-32 11.5 1.5 4.0 1.1 5.49E+06 3.17E−01 1-20 5.7 3.9 1.0 0.8 5.17E+02 6.95E−01 1-28 1.0 1.1 1.1 1.2 1.23E+08 9.05E+00 1-48 2.5 2.1 0.8 0.8 5.56E+07 9.11E+00 1-24 12.9 11.0 1.1 1.3 1.94E+08 1.46E+01 1-6  1.8 1.3 1.1 0.8 4.49E+08 2.08E+01 1-17 25.1 20.1 1.6 1.3 3.92E+08 2.63E+01 1-49 1.0 1.0 0.8 0.8 6.00E+08 3.22E+01 1-71 11.6 2.0 5.4 1.4 3.69E+08 4.03E+01 1-42 22.7 20.8 1.4 1.0 9.10E+08 1.03E+02

TABLE 6C SARS-CoV-2 Carterra SPR Kinetics Ranked by K_(D) S1- S1- ka kd K_(D) Rmax IgG Aero S1 RBD-Fc S1-Fc RBM-Fc (M-1 s-1) (s-1) (nM) (RU) 2-10 38.9 39.9 9.4 1.2 2.08E+05 1.15E−04 0.6 20 2-5  38.3 35.9 24.3 1.1 9.39E+04 2.59E−04 2.8 39 1-13 4.8 4.3 0.9 1.2 2.17E+05 1.38E−03 6.4 23 2-2  39.4 39.6 4.7 1.1 7.74E+04 9.06E−04 11.7 131 1-27 1.5 1.9 1.3 1.6 2.27E+05 2.85E−03 12.5 39 1-68 6.7 5.8 3.9 1.0 2.46E+06 8.75E−02 35.6 73 1-30 16.8 1.7 5.6 1.4 4.39E+04 1.64E−03 37.2 98 1-31 30.4 1.3 15.7 1.2 2.05E+04 7.62E−04 37.2 256 1-6  1.8 1.3 1.1 0.8 4.49E+08 2.08E+01 46.3 87 1-49 1.0 1.0 0.8 0.8 6.00E+08 3.22E+01 53.6 72 1-32 11.5 1.5 4.0 1.1 5.49E+06 3.17E−01 57.8 112 1-17 25.1 20.1 1.6 1.3 3.92E+08 2.63E+01 67.1 46 1-36 10.1 1.2 1.1 0.8 1.14E+05 7.85E−03 68.9 150 1-28 1.0 1.1 1.1 1.2 1.23E+08 9.05E+00 73.5 58 1-24 12.9 11.0 1.1 1.3 1.94E+08 1.46E+01 75.5 48 1-25 3.6 2.7 1.0 0.8 1.98E+06 1.56E−01 78.9 46 1-35 21.6 1.8 1.4 1.6 5.90E+04 5.43E−03 91.9 341 1-71 11.6 2.0 5.4 1.4 3.69E+08 4.03E+01 109.3 113 1-42 22.7 20.8 1.4 1.0 9.10E+08 1.03E+02 113.4 68 1-67 18.6 11.6 2.5 1.3 7.36E+04 8.86E−03 120.4 22 1-7  6.8 3.3 1.7 1.6 1.34E+06 1.70E−01 127.1 31 1-10 17.4 17.4 1.3 1.1 1.04E+06 1.47E−01 141.7 27 1-48 2.5 2.1 0.8 0.8 5.56E+07 9.11E+00 163.8 64 1-3  1.6 1.8 1.5 1.5 1.42E+06 3.04E−01 214.6 87 1-11 4.8 4.8 0.9 1.0 5.92E+05 1.43E−01 240.9 53 1-23 5.1 3.6 1.6 1.6 5.06E+05 1.59E−01 314.6 128 1-15 2.5 1.4 1.0 0.8 4.49E+05 1.56E−01 346.9 79 1-12 1.7 1.7 1.3 1.7 3.59E+05 1.34E−01 372.5 112 1-69 1.1 1.5 0.9 1.2 3.08E+05 1.23E−01 398.4 66 1-7  4.5 2.7 1.3 1.2 2.09E+05 1.55E−01 742.5 160 1-4  1.0 1.4 0.9 1.1 4.20E+04 1.24E−01 2946.4 385 1-29 1.1 0.9 1.0 0.9 5.35E+02 1.97E−03 3684.3 1206 1-2  1.8 1.9 1.7 1.7 1.58E+03 2.72E−02 17228.5 1652 1-5  1.5 1.6 1.2 1.4 2.15E+03 5.40E−02 25170.1 4457 1-47 8.1 5.5 1.2 0.9 6.32E+03 2.40E−01 37971.0 5497 1-20 5.7 3.9 1.0 0.8 5.17E+02 6.95E−01 1344113.2 64406

TABLE 6D ACE2 Carterra SPR Kinetics Ranked by Off-Rate ka IgG (M-1 s-1) kd (s-1) 4-29  1.66E+05 4.20E−04 4-33 2.29E+05 5.52E−04 4-89 2.04E+06 6.11E−04 4-18 6.61E+05 6.14E−04 4-6  4.84E+05 6.79E−04 4-64 2.90E+06 7.00E−04 4-2  1.40E+06 9.60E−04 4-49 2.91E+06 9.80E−04 4-45 8.03E+05 9.88E−04 4-41 1.80E+05 1.00E−03 4-63 6.10E+05 1.05E−03 4-73 2.27E+05 1.47E−03 4-52 1.26E+05 1.49E−03 4-5  3.22E+03 1.53E−03 4-12 2.51E+05 1.80E−03 4-14 1.32E+05 1.92E−03 4-46 7.87E+04 1.95E−03 4-7  1.61E+05 1.96E−03 3-15 1.53E+05 2.06E−03 4-67 9.39E+04 2.14E−03 4-56 1.30E+05 2.37E−03 3-3  3.28E+05 2.38E−03 4-57 3.07E+05 2.39E−03 3-14 1.72E+03 2.50E−03 4-69 9.94E+04 2.56E−03 4-78 2.47E+05 2.63E−03 4-3  5.33E+04 2.68E−03 4-34 5.25E+05 2.73E−03 4-20 3.54E+04 2.76E−03 4-31 2.17E+05 2.77E−03 4-74 2.48E+05 2.85E−03 4-61 3.48E+05 2.86E−03 4-25 7.87E+04 3.03E−03 4-82 3.01E+05 3.33E−03 4-62 2.45E+05 3.65E−03 4-21 3.16E+04 4.18E−03 4-76 1.35E+05 4.28E−03 4-75 2.99E+05 4.78E−03 3-6  2.23E+05 4.88E−03 3-8  1.14E+05 5.09E−03 3-7  4.69E+05 5.20E−03 3-9  8.36E+04 5.69E−03 4-32 1.26E+05 5.74E−03 3-12 1.55E+04 6.49E−03 4-9  2.86E+05 6.81E−03 4-95 4.15E+05 7.72E−03 3-11 2.69E+05 9.45E−03 3-13 8.09E+04 1.02E−02 4-15 5.54E+05 1.10E−02 4-39 1.36E+05 1.37E−02 3-10 2.22E+03 2.00E−02 4-42 8.79E+06 1.16E−01

TABLE 6E ACE2 Carterra SPR Kinetics Ranked by K_(D) ka kd K_(D) Rmax IgG (M-1 s-1) (s-1) (nM) (RU) 4-64 2.90E+06 7.00E−04 0.2 115 4-89 2.04E+06 6.11E−04 0.3 66 4-49 2.91E+06 9.80E−04 0.3 71 4-2  1.40E+06 9.60E−04 0.7 70 4-18 6.61E+05 6.14E−04 0.9 121 4-45 8.03E+05 9.88E−04 1.2 148 4-6  4.84E+05 6.79E−04 1.4 147 4-63 6.10E+05 1.05E−03 1.7 89 4-33 2.29E+05 5.52E−04 2.4 98 4-29 1.66E+05 4.20E−04 2.5 72 4-34 5.25E+05 2.73E−03 5.2 85 4-41 1.80E+05 1.00E−03 5.6 154 4-73 2.27E+05 1.47E−03 6.5 231 4-12 2.51E+05 1.80E−03 7.2 84 3-3  3.28E+05 2.38E−03 7.3 340 4-57 3.07E+05 2.39E−03 7.8 388 4-61 3.48E+05 2.86E−03 8.2 294 4-78 2.47E+05 2.63E−03 10.7 118 4-82 3.01E+05 3.33E−03 11.1 158 3-7  4.69E+05 5.20E−03 11.1 105 4-74 2.48E+05 2.85E−03 11.5 166 4-52 1.26E+05 1.49E−03 11.8 110 4-7  1.61E+05 1.96E−03 12.2 257 4-31 2.17E+05 2.77E−03 12.8 280 4-42 8.79E+06 1.16E−01 13.2 64 3-15 1.53E+05 2.06E−03 13.5 151 4-14 1.32E+05 1.92E−03 14.5 290 4-62 2.45E+05 3.65E−03 14.9 111 4-75 2.99E+05 4.78E−03 16.0 87 4-56 1.30E+05 2.37E−03 18.2 264 4-95 4.15E+05 7.72E−03 18.6 97 4-15 5.54E+05 1.10E−02 19.8 106 3-6  2.23E+05 4.88E−03 21.9 162 4-67 9.39E+04 2.14E−03 22.8 130 4-9  2.86E+05 6.81E−03 23.8 109 4-46 7.87E+04 1.95E−03 24.7 81 4-69 9.94E+04 2.56E−03 25.8 59 4-76 1.35E+05 4.28E−03 31.8 144 3-11 2.69E+05 9.45E−03 35.1 113 4-25 7.87E+04 3.03E−03 38.5 78 3-8  1.14E+05 5.09E−03 44.6 161 4-32 1.26E+05 5.74E−03 45.6 66 4-3  5.33E+04 2.68E−03 50.3 117 3-9  8.36E+04 5.69E−03 68.0 176 4-20 3.54E+04 2.76E−03 77.9 76 4-39 1.36E+05 1.37E−02 100.7 193 3-13 8.09E+04 1.02E−02 126.2 77 4-21 3.16E+04 4.18E−03 132.2 39 3-12 1.55E+04 6.49E−03 420.2 106 4-5  3.22E+03 1.53E−03 473.6 196 3-14 1.72E+03 2.50E−03 1452.3 300 3-10 2.22E+03 2.00E−02 8999.0 1681

Example 5. SARS-CoV-2 and ACE Variants

SARS-CoV-2 and ACE variant antibodies were tested for specificity and affinity.

Recombinant S1 Protein (Acros Biosystems Cat. No. S1N-S52H5) was passively immobilized on a 384 well ELISA plate and blocked with BSA. The S1 Panel antibodies were diluted from 50 nM to 0.0076 nM and incubated with the blocked plate. Antibody binding was detected using Goat-anti-Human-HRP secondary and developed with HRP substrate (list here). The absorbance signal was plotted as % of maximal binding and fitted to determine the EC50 of each antibody using GraphPad Prism.

Exemplary data for affinity of SARS-CoV-2 variant 2-6 is seen in FIGS. 11A-11B and ACE2 variants 3-7 (FIG. 12A), 4-49 (FIG. 12B), and 4-55 (FIG. 12C). The binding of SARS-CoV-2 panel of antibodies was measured as seen in FIG. 13 and Tables 7A-7F below.

TABLE 7A SARS-CoV-2 Variants EC50 Antibody EC50 (nM) 1-31 0.03139 2-6  0.03364 ACRO 0.04831 1-34 0.06522 2-2  0.07992 1-27 0.09283 2-8  0.1029 1-22 0.1248 1-32 0.1406 1-16 0.1435 1-12 0.1585 2-5  0.1615 CR3022 0.1657 1-53 0.1691 1-30 0.2084 1-28 0.2224 1-71 0.2673 1-20 0.3236 1-4  0.4216 1-35 0.4922 1-47 0.5893 1-5  0.774 2-4  0.8792 1-3  0.9724 1-21 1.003 2-19 1.257 1-51 1.465 1-19 1.706 1-42 1.742 2-2  1.789 2-1  1.894 1-33 3.006 2-13 5.139 2-11 6.921 2-15 8.509 2-7  10.09 1-26 11.93 1-24 12.86 1-49 13.04 1-10 18.31 1-1  21.87 1-8  25.09 1-7  26.94 1-72 29.13 1-17 33.17 1-36 34.86 1-73 43.58 2-10 46.43 1-9  46.88 2-17 51.86 1-52 57.88 2-18 74.71 1-29 83.41 2-12 95.94 1-25 107 2-9  118.3 1-23 123.9 1-48 296 2-14 854.7

TABLE 7B SARS-CoV-2 Variants Frequency and ELISA Data ELISA IgG Freq. (Avg) 1-21 1 47.6 1-22 3 40.6 1-30 1 29.5 1-35 3 28.6 1-17 79 27.4 1-27 1 27.2 1-12 2 25.7 1-2  14 24.2 1-3  2 23.9 1-23 1 23.1 1-7  4 22.5 1-31 1 20.7 1-4  1 20.6 1-8  2 19.3 1-9  2 18.5 1-32 1 17.9 1-33 1 17.6 1-24 1 32.9 1-5  1 20.6 1-28 2 17.7 1-10 1 16.9 1-26 1 19.5 1-13 1 28.2 1-14 1 21.7 1-6  1 20.8 1-20 3 26.0 1-29 1 23.8 1-1  1 32.5 1-19 1 22.3 1-16 1 22.1 1-34 1 28.7 1-18 1 22.7 1-11 1 33.2 1-25 1 27.9 1-36 1 23.6 1-15 1 24.8 1-51 1 7.1 1-52 1 3.5 1-53 1 21.7

TABLE 7C SARS-CoV-2 S1 Variants Inhibitor ELISA DB/S1 DB/S-T DC/S1 DC/S-T IC50 Fc/S1 Fc/S-T IgG Freq (Avg) K_(D) (nM) K_(D) (nM) K_(D) (nM) K_(D) (nM) (nM) K_(D) (nM) K_(D) (nM)f 1-21 1 47.6 6.7 1-22 3 40.6 73.2 1-30 1 29.5 37.2 4.7 475861.6 25.3 1-35 3 28.6 91.9 569.8 47.5 16.7 209.2 139.4 0.5 1-17 79 27.4 67.1 6649.2 10.0 1-27 1 27.2 12.5 5519.6 9.6 9.6 1-12 2 25.7 372.5 10.6 33.0 6.1 14.0 1-2  14 24.2 17228.5 304.3 1-3  2 23.9 214.6 423.0 252.8 5306.9 15.7 10.0 1-23 1 23.1 314.6 1-7  4 22.5 127.1 1-31 1 20.7 37.2 14.4 9.2 17.5 1-4  1 20.6 2946.4 6.6 659.2 129.2 25.5 12.3 1-8  2 19.3 97.3 1-9  2 18.5 282.4 1-32 1 17.9 57.8 14.8 2979.8 1-33 1 17.6 8.1 1739312.4 1-24 1 32.9 75.5 2043.7 1-40 2 22.9 1-5  1 20.6 25170.1 1155.7 1-28 2 17.7 73.5 13.4 520.3 96.6 3236.7 8.6 1-10 1 16.9 141.7 17.7 1-26 1 19.5 8.0 1-13 1 28.2 6.4 1-14 1 21.7 8.1 1-6  1 20.8 46.3 684.2 1-20 3 26.0 1344113.2 34.4 145.0 10.3 17.3 1-29 1 23.8 3684.3 36.1 19.3 1-1  1 32.5 1-19 1 22.3 85.4 0.0 14.3 18.6 1-16 1 22.1 2282.0 4487.3 1.7 178.8 2.2 1-34 1 28.7 8.2 623.6 13.4 1.4 1-18 1 22.7 1-11 1 33.2 240.9 30.2 1-25 1 27.9 78.9 3.0 6.1 1-36 1 23.6 68.9 3.9 9.3 33.2 1-15 1 24.8 346.9 1-51 1 7.1 1-52 1 3.5 739.8 1-53 1 21.7 1426.0 2-16 1 7.1 433.4 2-17 1 3.5 2-18 1 43.0 2-19 1 21.7 2-2  1 12.8

TABLE 7D SARS-CoV-2 S1 Variants Frequency and ELISA Data IgG Freq. ELISA(Avg) 2-1  1 45.3 2-10 1 43.8 2-5  46 30.8 2-2  2 23.4 2-4  1 15.5 2-6  5 22.1 2-11 3 28.1 2-12 1 18.2 2-13 1 19.1 2-14 1 17.2 2-7  1 25.3 2-8  1 32.4 2-15 1 13.7 2-9  1 14.1 2-16 1 7.1 2-17 1 3.5 2-18 1 43.0 2-19 1 21.7 2-2  1 12.8

TABLE 7E SARS-CoV-2 S1 Variants Inhibitor ELISA DB/S1 DB/S-T DC/S1 DC/S-T IC50 Fc/S1 Fc/S-T IgG Freq (Avg) K_(D) (nM) K_(D) (nM) K_(D) (nM) K_(D) (nM) (nM) K_(D) (nM) K_(D) (nM)  2-10 1 43.8 0.6 125.6 2-5 46 30.8 2.8 17.3 4.2 1.9 90.2 2-2 2 23.4 11.7 1.2 1.4 3.6 58.3 0.8 2-4 1 15.5 4337.7 2-6 5 22.1 3.0 563.8 0.4 32.3 0.01  2-11 3 28.1 3.1 90.0 284.5  2-12 1 18.2 6.4 63.8 1.0 3.2  2-13 1 19.1 45.0  2-14 1 17.2 2.5 34.8 2-7 1 25.3 252.5 2-8 1 32.4 115.1 33.4 47.4 12.2 52.8  2-15 1 13.7 3.5 4.7 2-9 1 14.1 23.2 23582.5

TABLE 7F Antibody Panel ELISA Binding Titrations (EC50) ANTIBODY EC50 (nM) 2-8  0.08001 1-35 0.09604 1-3  0.133 2-5  0.1332 1-27 0.1479 1-31 0.2035 2-6  0.283 1-2  0.523 1-34 0.5584 2-2  0.612 1-67 0.9402 1-16 1.409 1-12 2.15 1-28 2.284 1-4  2.559 1-1  4.157 1-19 4.413 1-22 6.548 1-5  7.833 1-42 7.92 2-15 7.92 1-49 8.669 1-53 10.25 2-9  12.58 1-33 17.5 1-26 48.46 2-29 63.43 1-7  95.66 1-25 95.66 1-51 98.17 2-17 100 2-2  100

The data for ACE2 variant antibodies is seen in Tables 8A-8B.

TABLE 8A ACE2 Variants Frequency and ELISA Data IgG Freq. ELISA (Avg) 3-10 1 17.4 3-4  1 15.2 3-7  1 17.1 3-1  7 18.4 3-5  4 18.1 3-6  1 24.0 3-15 1 13.1 3-3  12 22.0 3-11 1 13.7 3-8  1 19.9 3-2  1 15.7 3-12 1 19.1 3-14 1 24.0 3-9  1 26.0 3-13 1 24.9 3-16 1 8.0 3-17 1 12.3 3-18 1 9.8 3-19 1 5.4 3-2  1 3.0 3-21 1 6.2 3-22 1 6.2 3-23 1 3.7 3-24 1 6.5 3-25 1 5.3 3-26 1 4.1 3-27 1 11.7 3-28 1 3.5 3-29 1 5.0

TABLE 8B ACE2 Variants Frequency and ELISA Data IgG Freq. ELISA (Avg) 4-51 1 52.0 4-52 1 49.3 4-53 1 41.1 4-54 1 40.7 4-49 21 35.1 4-55 1 29.0 4-39 1 28.0 4-56 1 22.9 4-33 1 20.2 4-57 1 19.6 4-25 1 17.0 4-58 1 15.1 4-69 2 21.8 4-18 4 20.4 4-63 2 24.7 4-73 2 20.2 4-43 2 22.9 4-72 2 20.6 4-5  2 26.6 4-67 4 20.0 4-41 2 33.9 4-6  2 22.9 4-16 2 38.7 4-32 2 21.2 4-75 2 37.5 4-37 2 24.1 4-15 2 35.4 4-42 2 35.9 4-17 2 28.1 4-35 2 26.4 4-20 2 31.0 4-31 18 24.8 4-14 4 30.3 4-7  2 35.4 4-76 2 23.1 4-89 2 39.4 4-64 4 23.7 4-3  2 41.6 4-45 2 37.8 4-6  2 27.8 4-11 2 25.1 4-44 2 23.3 4-82 2 27.1 4-40 2 25.3 4-62 2 27.7 4-74 2 25.4 4-78 2 21.1 4-46 2 25.3 4-2  2 25.7 4-21 2 22.6 4-9  2 24.2 4-61 2 25.1 4-12 2 21.8 4-29 2 22.0 4-34 2 25.4 4-47 2 20.9 4-95 2 23.2 4-36 2 20.1 4-98 1 9.1 4-99 1 4.8 4-1  1 6.5  4-101 1 17.4  4-102 1 14.4  4-103 1 9.0  4-104 1 5.3  4-105 1 7.8  4-106 1 5.4  4-107 1 7.5  4-108 1 10.0  4-109 1 17.5 4-11 1 23.3  4-111 1 14.0  4-112 1 11.1  4-113 1 8.9  4-114 1 9.9  4-115 1 26.4  4-116 1 12.6  4-117 1 12.4  4-118 1 34.9  4-119 1 28.6 4-12 1 17.9  4-121 1 36.2  4-122 1 10.6  4-123 1 14.2  4-124 1 29.3  4-125 1 22.2  4-126 1 14.6  4-127 1 16.1  4-128 1 5.3  4-129 1 6.8 4-13 1 23.1  4-131 1 37.9  4-132 1 10.9  4-134 1 14.7  4-135 1 7.3  4-136 1 16.3  4-137 1 4.8  4-138 1 21.3  4-139 1 34.3 4-14 1 43.7  4-141 1 15.0  4-142 1 14.4  4-143 1 8.4  4-144 1 11.8  4-145 1 9.5  4-146 1 7.8  4-147 1 6.4  4-148 1 20.6  4-149 1 14.3 4-15 1 22.3  4-151 1 15.1

VERO C1008 [Vero 76, clone E6, Vero E6] (ATCC® CRL-1586™) are derived from the kidney of an African green monkey and are commonly used mammalian continuous cell lines. These cells are known to express ACE2 and have been used for SARS-CoV-2 neutralization assays. To assess the binding efficiency of this panel of antibodies, each antibody was incubated with 10⁵ VERO E6 cells at 100 nM, a labeled secondary antibody was used to measure binding using flow cytometry. The binding of each antibody was compared to a baseline value, consisting of secondary antibody alone, to derive a Mean Fluorescence Intensity (MFI) over baseline (MFI/Baseline). Data for antibody variant 4-23 is seen in FIG. 14. Data for variant 3-1 is seen in FIG. 15A.

The entire panel shows varying degrees of specific binding to VERO E6 cells as in Tables 9A-9B. S1 Fc fusion protein and S1 RBD Fc fusion (expressed in-house) were added as positive controls for ACE2 binding.

TABLE 9A ACE2 Variant Binding MFI/ Antibody MFI Baseline 4-15 40911 103.1  4-101 30450 76.7 4-3  23871 73.7 4-44 23486 72.5 4-89 22369 69.0  4-142 25078 63.2 4-12 24964 62.9  4-148 23582.5 59.4 4-75 18861 58.2 4-52 18184 56.1 4-50 17964 55.4 4-25 17603 54.3  4-138 21564 54.3 4-35 17460 53.9 4-39 17390 53.7 4-49 17249 53.2  4-119 21061.5 53.1  4-137 20784.5 52.4 4-64 16834 52.0 4-37 15775 48.7 4-21 15024 46.4 4-68 14963 46.2 4-97 14963 46.2 4-11 14782 45.6 4-85 14194 43.8

TABLE 9B ACE2 Variant Binding MFI/ Antibody MFI Baseline 4-67 13852 42.8  4-144 16698 42.1 4-63 13247 40.9  4-114 15946.5 40.2 4-47 12720 39.3 4-17 12720 39.3 4-43 12413 38.3 4-9  12115 37.4 4-28 11968 36.9 4-32 11823 36.5 4-4  11538 35.6 4-29 11492 35.5 4-3  11352 35.0 4-73 10989 33.9 4-62 10856 33.5 4-54 10812 33.4 4-16 10812 33.4 4-69 10509 32.4 4-77 10382 32.0 4-14 9928 30.6 4-53 9117 26.5  4-121 4882 12.3 4-14 2876 7.2 S1 Fc 55333 160.9 Fusion S1 RBD Fc 26102 75.9

Purified antibodies were quantified by Unchained Lunatic and analyzed by Perkin Elmer LabChip System, CE-SDS (R, purity) for quality control. Data is seen in FIGS. 15B-15Ds Tables 10A-10D. Table 10D shows kinetic data for the variant antibodies collected using the Carterra LSA instrument (Fc, Fc-capture; DC, Direct-capture). The variant antibodies exhibit very high specificity and affinity to their antigen targets with affinities in the picomolar to nanomolar range.

TABLE 10A ACE2 Variant Quality MFI/ Antibody MFI Baseline 3-10 170440 495.5 4-15 40911 103.1 4-6  29246 90.3  4-101 30450 76.7 4-3  23871 73.7 4-44 23486 72.5 4-61 22921 70.7 4-89 22369 69.0 4-65 21742 67.1  4-142 25078 63.2 4-12 24964 62.9  4-148 23582.5 59.4 4-75 18861 58.2 4-52 18184 56.1 4-50 17964 55.4 4-25 17603 54.3  4-138 21564 54.3 4-35 17460 53.9 4-39 17390 53.7 4-49 17249 53.2  4-119 21061.5 53.1  4-137 20784.5 52.4 4-64 16834 52.0 4-37 15775 48.7 4-21 15024 46.4

TABLE 10B ACE2 Variant Quality MFI/ Antibody MFI Baseline 4-68 14963 46.2 4-97 14963 46.2 4-11 14782 45.6 3-13 15647 45.5 4-85 14194 43.8 4-67 13852 42.8  4-144 16698 42.1 4-63 13247 40.9 4-43 12413 38.3  4-114 15946.5 40.2 4-47 12720 39.3 4-17 12720 39.3 4-54 10812 33.4 3-4  11261 32.7 3-2  10132 29.5 3-7  9117 26.5 3-15 8440 24.5 3-3  7174 20.9  4-121 4882 12.3 3-5  4030 11.7 3-6  3746 10.9 4-14 2876 7.2  4-118 1091.5 2.7 S1 Fc 55333 160.9 Fusion S1 RBD 26102 75.9 Fc Fusion

TABLE 10C Ab IC50 (nM) 3-7  101.1 3-5  4.929 3-6  60.02 3-3  0.9157 4-52 0.3499 4-54 1.995 4-49 58.01 4-39 1.148 4-17 0.7208  4-101 0.5675  4-121 0.9101  4-140 3.07

TABLE 10D K_(D), ACE2 K_(D), ACE2 Antibody Fc DC 3-7  3.4 32.6 3-5  6.7 >1000 3-6  5.6 >1 3-3  7.3 NA 4-52 11.5 557.1 4-54 NA 644.8 4-49 0.3 228.6 4-39 17.5 NA 4-17 18.8 30.6  4-101 NA 5.8  4-118 NA NA  4-121 NA NA  4-140 NA 8.9

The SARS-CoV-2 and ACE2 variant antibodies were also assayed for affinity (data not shown). As a negative control, Trastuzumab was found not to bind to ACE2.

Competition ELISAs were performed on the variant antibodies. Typical data for SARS-CoV-2 S1 RBD and ACE2 competition ELISA is seen in FIGS. 16A-16B. Data for competition ELISA for a first set of SARS-CoV-2 S1 RBD and ACE2 variant antibodies is seen in FIGS. 17A-17B and FIG. 18A. SARS-CoV-2 variant antibodies with high potency in order of potency included variant 2-2, Acro mAb (1.5333), variant 2-5, variant 1-12, and variant 2-9. ACE variant antibodies with high potency in order of potency included variant 4-52, variant 4-17, variant 4-39, Acro mAb (1.533), variant 4-54, and variant 3.5. Data for competition ELISA for a second set of ACE2 variant antibodies is seen in FIG. 18B. Variant antibodies with high potency in order of potency included variant 4-101, variant 4-140, variant 4-121, variant 4-118, and Acro mAb (2.76 nM). FIGS. 18C-18D show the SARS-CoV-2 variant antibodies show potent neutralization.

Anti-ACE2 inhibitors were also identified using ELISA as seen in FIG. 19. Variant antibodies with high potency in order of potency included variant 4-52, variant 4-17, variant 4-14, variant 4-139, variant 4-39, variant 4-54, and Acro mAb (1.887 nM). Inhibition assays were also performed as seen in FIG. 20.

SARS-CoV-2 variant antibodies were assayed for Vero inhibition using FACS. Briefly, Vero cells stripped with Cell Stripper (˜20 minutes with 90% viability after removal). Cells were plated at 0.1×10⁶ cells per well. Stock solution of the variant antibodies were at 200 nM titrated 1:3. SARS-CoV-2 S protein RBD, SPD-C5259 were made up at 6 ug/mL. Variant antibody titrations were mixed 1:1 with 6 ug/mL S protein (50 uL IgG: 50 uL S protein). 100 uL of the mixture were added to cells and then incubated on ice for 1 hour. The cells were washed 1× followed by addition of 50 uL of goat anti-mouse secondary made up at 1:200. The cells were then incubated on ice for 1 hour in the dark, washed three times, and the plates were then read. Data for SARS-CoV-2 variant antibodies is seen in FIGS. 21A-21D, FIGS. 22A-22E, and Tables 10E-10F. As seen in the data, several variant antibodies blocked labeled S1 RBD from binding to ACE2 on the Vero cells including variants 2-8, 2-5, 2-2, 2-4, and 1-63.

TABLE 10E Antibody IC50 (nM) Acro Anti-S1    2.7  1-30 NC  1-35 NC  1-12 NC  1-31 NC  1-63 106.6 2-5 4.4 2-2 3.0 2-4 46.3 2-6 NC 2-8 19.5

TABLE 10F S1 Monomer S Trimer (nM) (nM) 1-31 0.22 0.80 1-30 0.67 4.02 1-35 0.15 0.76 1-12 2.08 0.61 1-63 1.40 14.39 2-8  1.52 7.08 2-5  0.17 0.59 2-2  0.13 0.64 2-4  1.58 10.18 2-6  0.07 0.43

A summary of epitope binning for SARS-CoV-2 variant antibodies is seen in Table 10G below.

TABLE 10G SARS-CoV-2 Epitope Binning Aero Abeam ID mAb 2-2 CR3022 2-5 2-8 2-11 1-32 1-16 2-6 1-35 *Acro 0 0 2 1 1 1 1 1 1 1 mAb *2-2 0 0 0 0 0 0 2 0 2 1 Abeam 2 0 0 0 0 1 1 2 2 2 CR3022 *2-5 1 0 0 0 0 1 1 1 1 1 *2-8 1 0 0 0 0 1 1 1 1 1 2-11 1 0 0 0 0 0 1 2 1 1 **1-32 2 1 3 1 2 1 0 0 1 1 1-16 1 1 2 2 1 1 1 0 0 0 2-6 2 2 3 2 2 2 1 0 0 0 1-35 1 1 2 2 1 1 1 0 0 0 *Anti-S1 inhibiting IgG in FACS (Vero E6) **Anti-S1 inhibiting IgG in ELISA (soluble ACE2)

The variant antibodies were also measured in binding against other coronaviruses. Data shows that the variant antibodies do not bind significantly to S1 HCoV-229E (Sino), S1 HCoV-HKU1 (Sino), S1 HCoV-NL63 (Sino), or S1 HCoV-OC43 (Sino) (data not shown).

BluDiagnostics initial testing was performed. Results as seen in FIG. 23 indicated that variant 2-6 binding was similar to CR3022, which is a positive control.

The data shows that the SARS-CoV-2 and ACE2 variant antibodies have high specificity and affinity to their antigen targets with affinities in the picomolar to nanomolar range.

Example 6. SARS-CoV-2 S1 and ACE2 Variants

SARS-CoV-2 S1 and ACE2 variants were generated and panned as described in Examples 4 and 5.

FIG. 7 shows a schema of the panning strategy. Biotinylated antigen was bound to streptavidin coated magnetic beads at a density of 100 pmol antigen per mg of beads (Thermo Fisher #11206D). Phage libraries were blocked with 5% BSA in PBS. Following magnetic bead depletion for 1 hour at room temperature (RT), the beads were removed, and phage supernatant was transferred to 1 mg of antigen-bound beads in 1 ml PBS and incubated at RT with rotation for 1 hour. Non-binding clones were washed away by addition of 1 ml PBST, increasing the number of washes with each panning round. Trypsin was used to elute the phage bound to the antigen-bead complex. Phage were amplified in TG1 E. coli for the next round of selection. This selection strategy was repeated for four rounds, with successively lower amounts of antigen per round. Following all four selection rounds, 400 clones from each of round 2, 3, and 4 were selected for phage expression and phage ELISA screening. Data from the panning is seen in Table 11.

TABLE 11 Panning Data Antibody Library R1 R2 R3 R4 R5 5 Target S1 S1 S1 S1 S1 Input Titer 2.0 × 10¹³ 1.2 × 10¹³ 7.0 × 10¹² 1.0 × 10¹³ Output Titer 3.5 × 10⁶  8.0 × 10⁶  4.0 × 10⁷  3.2 × 10⁸  6 Target S1 S1 S1 S1 S1 Input Titer 2.0 × 10¹³ 1.2 × 10¹³ 1.0 × 10¹³ 1.0 × 10¹³ Output Titer 2.5 × 10⁷  3.6 × 10⁶  6.0 × 10⁷  1.2 × 10⁸ 

To test for binding to SARS-CoV-2 S1, phage were expressed from each picked colony by KO7 superinfection in 384 well microtiter plates. Phage containing supernatant was blocked by 1:1 addition of 4% non-fat milk (NFM). Assay plates were prepared by passive immobilization of 0.4 μg antigen in 384-well Maxisorp plates (Thermo Fisher #464718) and then blocked with 4% NFM. Following 3× wash in PBST, blocked phage supernatant was incubated for 1 hour at RT. After 3× wash in PBST, 0.3 μg/ml anti-M13-HRP (Sino Biological #11973-MM05T-H) was aliquoted for 1 hour incubation at room temperature. Binding of phage-displayed antibody was determined by absorbance at 450 nm with 3,3′,5,5′-tetramethylbenzidine (Thermo Fisher #34029). Phage that bound to antigen with 3× over background of human Fc protein were identified as potential binders for sequencing analysis. DNA was amplified by rolling circle amplification from glycerol stocks of each clone and submitted for Sanger sequencing (Genewiz) to capture the VH and VL domains. FIGS. 24A-24B shows phage ELISA data from panning data for antibody 5 and antibody 6. For Antibody 5 variants, 116 unique clones and 68 unique CDRH3 were identified. For Antibody 6 variants, 136 unique clones and 112 CDRH3 were identified.

SARS-CoV-2 variants were tested for specificity using a phage ELISA as described above. The antigens used included Acro SARS-CoV-2 (COVID-19) S1 protein and CV S-protein construct 6 trimer TP31001F. the antigens were coated at 1 ug/mL, 20 uL per well in 384 NUNC plate. Purified antibodies were prepared in in PBS-Tween at 100 nM, 10 nM, 1 nM, 0.1 nM. Secondary detection was performed using MonoRab™ Rabbit Anti-Camelid VHH Antibody [HRP], mAb (GenScript cat # A01860-200) used at 1:10,000. Data from the phage ELISA is seen in FIGS. 25A-25H for antibody 5 variants and FIGS. 26A-26I for antibody 6 variants. FIGS. 27A-27B show ELISA data for select antibody 6 variants. FIGS. 28A-28F shows phage ELISA for antibody 5 variants using 1 nM and 0.1 nM concentrations of antibodies. FIGS. 29A-29J shows phage ELISA for antibody 6 variants using 1 nM and 0.1 nM concentrations of antibodies. The SARS-CoV-2 variant antibodies were also assayed for affinity. Direct coupling refers to direct amine coupling of the antibody to the chip surface for the SPR assays. Tables 12-13 show SPR data for antibody 5 variants and antibody 6 variants.

TABLE 12 New S1 K_(D) S Trimer Competition Name (nM) K_(D) (nM) Factor 5-1  15.1 0.4 10.01 5-2  54.2 1.5 2.29 5-3  64.6 5.6 0.87 5-4  — — 0.83 5-5  61.9 4.0 6.55 5-6  29.1 0.3 2.58 5-7  — — 3.43 5-8  62.2 3.8 7.11 5-9  40.6 0.7 3.27 5-10 588.0  5.4 0.90 5-11 — 0.0 4.79 5-12 96.6 4.8 2.55 5-13 37.5 3.8 1.97 5-14 — — 0.84 5-15 96.2 2.3 6.22 5-16 50.2 1.9 1.39 5-17 3628.8  18.9  0.88 5-18 — — 0.80 5-19 80.1 0.1 4.56 5-20 14.3 1.1 12.44 5-21 1069.3  10.0  1.14 5-22 108.7  7.2 2.06 5-23 84.8 4.2 0.95 5-24 34.6 2.2 4.90 5-25 43.3 20.1  0.82 5-26 21846.3  — 0.81 5-27 92.9 109.8  0.93 5-28 40.0 1.0 3.61 5-29 42.4 1.0 7.08 5-30 53.1 1.8 2.04 5-31 — — 0.78 5-32 22.4 0.1 0.79 5-33 38.0 0.2 0.84 5-34 — — 5.69 5-35 — 16.0  0.78 5-36 — — 0.83 5-37 30.2 1.8 8.19 5-38 28.5 0.7 8.41 5-39 117.5  37.6  1.11 5-40 — — 0.86 5-41 243.8  4.1 3.64 5-42 115.9  0.6 0.91 5-43 — — 0.89 5-44 59.2 2.4 6.02 5-45 — — 0.96 5-46 255.7  7.2 10.49 5-47 27.7 0.7 11.67 5-48 — — 0.83 5-49 74.5 3.4 5.01 5-50 60.5 3.8 5.09 5-51 25.5 0.0 1.03 5-52 99.0 0.9 2.86 5-53 — 683.6  0.83 5-54 — — 0.79 5-55 63.5 0.6 6.86 5-56 54.3 2.8 5.36 5-57 — 37.0  0.83 5-58 1679.6   3.5 0.93 5-59 113.3  6.4 4.55 5-60 29.4 0.8 7.85 5-61 — — 0.82 5-62 — — 0.84 5-63 10.5 0.4 1.62 5-64 346.5  221.2  0.84 5-65 352.7  421.0  0.94 5-66 — 98.9  1.00 5-67 22.1 1.0 10.95 5-68 111.0  4.8 4.58 6-1  35.8 1.2 5.38 6-2  29.9 1.2 3.14 6-3  12.4 0.0 9.51 6-4  45.8 0.5 2.71 6-5  24.9 0.8 4.33 6-6   6.4 67.7  0.97 6-7  — — 8.73 6-8  69.4 4.6 4.06 6-9  18.5 0.9 4.17 6-10 29.7 0.6 6.92 6-11 — — 4.26 6-12 50.2 1.4 2.56 6-13 25.3 0.6 3.20 6-14 134.7  465.9  0.83 6-15 — 9054.3   1.06 6-16 52.1 2.2 2.32 6-17 65.2 0.6 3.04 6-18 30.1 5.3 5.87 6-19 71.0 1.0 0.93 6-20 20.9 0.3 9.95 6-21 — — 0.83 6-22 25.6 1.8 2.35 6-23 59.3 0.3 4.30 6-24 29.9 0.2 1.26 6-25 248.0  5.8 0.80 6-26 38.7 0.1 6.41 6-27 — — 0.85 6-28 54.1 0.4 4.64 6-29 97.5 1.6 2.87 6-30 11.8 0.1 10.51 6-31 39.6 20.7  0.92 6-32 27.2 0.1 1.43 6-33 76.4 0.2 2.88 6-34 21.3 0.7 5.22 6-35 251.1  — 0.94 6-36 32.1 0.8 4.40 6-37 22.5 0.7 4.77 6-38 26.6 0.5 5.68 6-39 11.3 0.1 7.26 6-40 44.3 1.9 7.20 6-41 51.5 1.0 7.27 6-42 10.1 7.8 1.12 6-43 17.9 0.7 4.07 6-44  8.2 0.9 6.10 6-45 17.5 1.3 5.14 6-46 18.1 1.9 4.88 6-47 43.9 5.6 6.26 6-48 — — 0.93 6-49 58.2 2.2 1.07 6-50 — 67.6  1.05 6-51 35.2 0.8 0.82 6-52 31.2 1.1 2.77 6-53 139.7  24.2  0.88 6-54 143.7  0.9 6.84 6-55 25.2 0.3 7.98 6-56 — 14.9  3.31 6-57 205.3  0.7 6.63 6-58 20.7 1.0 2.96 6-59 — 27.6  2.21 6-60 20.1 0.1 12.61 6-61 — — 2.60 6-62 151.4  198.1  4.89 6-63 21.8 0.3 7.76 6-64 — 20.1  0.89 6-65 889.8  — 9.47 6-66 293.1  7.7 2.45 6-67 55.6 0.1 6.01 6-68 101.5  0.7 2.32 6-69 — — 0.82 6-70 35.9 1.1 1.41 6-71 155.2  0.6 2.77 6-72 92.8 2.0 2.08 6-73 103.2  0.5 7.99 6-74 73.9 498.2  0.90 6-75 181.0  1.0 3.56 6-76 33.5 1.8 9.96 6-77 24.6 3.5 6.84 6-78 18.9 0.4 9.27 6-79 157.8  0.0 0.78 6-80 33.7 0.8 3.04 6-81 12.9 3.9 11.92 6-82  7.1 0.6 1.35 6-83 163.2  4.4 4.09 6-84 82.6 0.7 0.89 6-85 15.0 0.5 6.47 6-86 25.0 0.9 3.07 6-87 33.4 2.5 3.68 6-88 308.2  2.3 8.17 6-89 — — 0.82 6-90 113.6  17.1  0.86 6-91 75.2 3.4 8.30 6-92 62.3 1.9 2.85 6-93 37.4 6.4 2.26 6-94 30.6 1.6 4.16 6-95 — 7.6 0.88 6-96 24.6 3.3 4.49 6-97 4070.9  57.9  1.26 6-98 — — 0.87 6-99 51.6 3.4 1.74  6-100  7.0 0.6 10.79  6-101 — — 0.90  6-102 45.7 0.9 0.90  6-103 23.6 1.0 1.41  6-104 — — 0.97  6-105 41.6 1.9 5.64  6-106 — 1072.2   0.94  6-107 24.1 0.5 3.20  6-108 69.4 0.3 0.99  6-109 48.7 12.2  10.03  6-110 15.6 0.3 4.59  6-111 98.6 4.4 4.23  6-112 3229.9  43.8  0.90

TABLE 13 S1 S Trimer MFI Fold VHH-Fc K_(D) (nM) K_(D) (nM) Decrease 6-6  6.4 67.70  0.97  6-100 7 0.60 10.79 6-82 7.1 0.60 1.35 6-44 8.2 0.90 6.1 6-42 10.1 7.80 1.12 5-63 10.5 0.40 1.62 6-39 11.3 0.10 7.26 6-30 11.8 0.10 10.51 6-3  12.4 0.00 9.51 6-81 12.9 3.90 11.92 5-20 14.3 1.10 12.44 6-85 15 0.50 6.47 5-1  15.1 0.40 10.01  6-110 15.6 0.30 4.59 6-45 17.5 1.30 5.14 6-43 17.9 0.70 4.07 6-46 18.1 1.90 4.88 6-9  18.5 0.90 4.17 6-78 18.9 0.40 9.27 6-60 20.1 0.10 12.61 6-58 20.7 1.00 2.96 6-20 20.9 0.30 9.95 6-34 21.3 0.70 5.22 6-63 21.8 0.30 7.76 5-67 22.1 1.00 10.95 5-32 22.4 0.10 0.79 6-37 22.5 0.70 4.77  6-103 23.6 1.00 1.41  6-107 24.1 0.50 3.2 6-96 24.6 3.30 4.49 6-77 24.6 3.50 6.84 6-5  24.9 0.80 4.33 6-86 25 0.90 3.07 6-55 25.2 0.30 7.98 6-13 25.3 0.60 3.2 5-51 25.5 0.00 1.03 6-22 25.6 1.80 2.35 6-38 26.6 0.50 5.68 6-32 27.2 0.10 1.43 5-47 27.7 0.70 11.67 5-38 28.5 0.70 8.41 5-6  29.1 0.30 2.58 5-60 29.4 0.80 7.85 6-10 29.7 0.60 6.92 6-2  29.9 1.20 3.14 6-24 29.9 0.20 1.26 6-18 30.1 5.30 5.87 5-37 30.2 1.80 8.19 6-94 30.6 1.60 4.16 6-52 31.2 1.10 2.77 5-56 54.3 2.77 5.36 5-8  62.2 3.80 7.11 6-91 75.2 3.45 8.30 6-73 103.2 0.52 7.99 5-34 — — 5.69 6-26 38.7 0.07 6.41 6-76 33.5 1.77 9.96

VHH-Fc antibodies targeting S1 were titrated 1:3 starting at 200 nM and mixed 1:1 with SARS-COV2-S1 RBD (mouse IgG2Fc tag). The RBD/VHH-Fc complex was added to Vero E6 cells expressing endogenous ACE2 receptor and incubated. Cells were subsequently washed and an anti-mouse secondary was used to measure binding of S1 RBD to ACE2, thus assessing the inhibition of S1. Over 60 clones demonstrated potent inhibition. Data is seen in FIGS. 30A-30C and Tables 14A-14B.

TABLE 14A Sample IC₅₀ [nM] 2-2  0.56 5-56 0.68 5-1  0.75 5-67 0.76 5-47 0.80 5-8  0.94 5-38 0.96 5-37 1.01 5-34 1.21 5-20 1.23 5-55 1.45 5-46 1.52 5-50 1.61 5-5  1.79 2-5  2.146 5-60 2.15 5-15 2.19 5-29 2.19 Acro Anti 3.80 S1 5-49 5.61 5-44 11.73

TABLE 14B Sample IC₅₀ [nM] 6-85 0.2044 2-2  0.56 6-63 0.74 6-3  0.74 6-78 0.7427 6-20 0.76 6-91 0.89 6-44 0.97 6-55 0.97 6-73 1.01 6-26 1.07 6-76 1.11 6-45 1.16 6-60 1.31 6-40 1.36 6-81 1.383 6-10 1.44 6-7  1.53 6-39 1.53  6-109 1.60 6-38 1.94 2-5  2.146 6-30 2.94 6-57 3.13 Aero Anti 3.49 S1 6-67 3.80 6-77 4.041  6-100 5.07 6-47 5.86 6-41 6.60 6-88 7.118  6-105 7.82 6-34 8.24 6-54 8.90 6-18 12.29 6-1  15.76 6-65 37.47

Antibody kinetics were measured for variants 2-5, 2-2, and 2-6 (FIG. 31A) and variants 1-12, 1-42, 1-20, and 1-19 (FIG. 31B). Data is seen in FIGS. 31A-31B. The data shows that the antibodies bind with nanomolar affinities. FIG. 31C shows percent neutralization for variants 1-12, 1-42 and 1-20. FIG. 31D shows percent neutralization for variants 1-12, 1-42 and 1-20 using live virus.

The ACE2 variant antibodies were measured for effects on ACE activity. Using a Sigma-Aldrich ACE activity assay kit (CS0002), ACE positive control were premixed with 1, 10, 100 nM anti-ACE2 mAb and read at 320 nm excitation, 405 nm emission, 5 min kinetics. The data is seen in FIG. 32 and shows the ACE2 variant antibodies do not inhibit enzyme activity.

Example 7. Neutralization of Live Virus

VHH-Fc antibodies targeting S1 were titrated 1:3 starting at 200 nM and mixed 1:1 with SARS-COV2-S1 RBD (mouse IgG2Fc tag). The RBD/VHH-Fc complex was added to Vero E6 cells expressing endogenous ACE2 receptor and incubated. Cells were subsequently washed and an anti-mouse secondary was used to measure binding of S1 RBD to ACE2, thus assessing the inhibition of S1. Over 60 clones demonstrated potent inhibition. The data is seen in FIGS. 33A-33B and Table 15A.

TABLE 15A Antibody EC50 (ug/mL) 6-63 0.06 6-3  0.06 2165 mAb* 0.08 5-1  0.10 6-60 0.15 6-55 0.21 5-20 0.27 1-20 0.37 5-34 0.54 6-85 0.84 6-76 1.08 6-73 1.46 1-42 2.03 1-12 2.10 6-26 2.97 6-20 5.03 6-78 8.26 2-6  11.77 2-5  18.31 2-2  67.57 1-63 106.90

FIG. 33B shows that variant 6-2 showed higher neutralization versus IgG in live virus. Variants 6-63, 6-3, and 5-1 showed comparable neutralization versus 2165 mAb derived from a COVID-19 subject.

FIGS. 33C-33E and Table 15B show data from VHH single domain antibodies in VSV-pseudotype SARS-CoV-2 neutralization assays. Variants 5-1, 6-3, and 6-63 showed improved neutralization in pseudovirus testing including in live virus FRNT (FIG. 33E). Variants 6-3, 6-60, 6-63, and 6-76 showed potent neutralization in live virus PRNT as seen in Table 15C and FIG. 33F. Data as seen in Table 15D and FIGS. 33G-33H show that variants 6-3, 6-63, and 1-20 exhibited potent neutralization in live virus PRNT.

TABLE 15B Antibody NC50 (ug/mL) 6-63 0.06 6-3  0.06 5-1  0.10 6-60 0.15 6-55 0.21 5-20 0.27 1-20 0.37 5-34 0.54 6-85 0.84 6-76 1.08 6-73 1.46 1-42 2.03 1-12 2.10 6-26 2.97 6-20 5.03 6-78 8.26 2-6  11.77 2-5  18.31 2-2  67.57 1-63 106.90

TABLE 15C Antibody PRNT90 (ng/mL) 5-1  15.6 5-20 3.9 5-34 15.6 6-26 62.5 6-60 <0.98 6-63 3.9 6-3  <0.98 6-55 62.5 6-76 3.9 6-78 250 6-20 15.6 6-73 250 6-85 62.5

TABLE 15D Antibody EC80 (ug/mL) 6-63 0.057861 6-3  0.115234 1-20 0.171875 6-60 0.236816 5-20 0.376 6-76 0.425781 6-55 0.445313 5-34 0.570313 6-42 0.734375 5-1  0.810547 1-12 0.855469 6-85 1.0625 5-38 1.5 5-67 1.566406 1-42 1.78125 6-73 2.015625 6-20 2.3125 5-47 2.457031 1-19 2.78125 6-44 3.15625 6-26 3.609375 6-45 4.015625 5-37 12.4375 6-78 13.75 5-63 14.1875 5-8  15.8125 6-6  24.375 6-13 25.6875 6-24 31.375 1-63 50.5 6-32 60.625 2-6  72.34043 6-22 103.25 5-56 104.75 2-5  106.5 6-82 107.75 5-32 180.1418 6-91 240.5 2-2  354.6099 5-51 387.9433

The variants were also tested in pseudovirus neutralization and live virus PRNT studies. Variants 5-20, 6-60, 6-63, and 6-3 showed potent neutralization in live virus PRNT as seen in FIG. 33I.

Example 8. In Vivo Evaluation of Variant Coronavirus Immunoglobulins

This Example assesses the variant coronavirus immunoglobulins in a Syrian hamster model (immunosuppressed) of COVID-19 disease.

8-10 week-old female Syrian hamsters were immunosuppressed using cyclophosphamide (140 mg/kg day 3 days before challenge and then 100 mg/kg every 4 days by i.p. route). Eleven groups of six hamsters per group were injected with antibody on day −1 relative to challenge by the intraperitoneal route (i.p.). On Day 0 all hamster were challenged with 1,000 PFU SARS CoV-2 Washington isolate by the intranasal route and weighed daily. % Weight change relative to starting weight was calculated. Pharyngeal swabs were collected on Days −1, 1, 4, 7, 9. Day 9 lungs were collected and homogenized for viral load. Groups are shown in Table 15E.

TABLE 15E Groups Diluent/ volume injected Group i.p. Convalescent plasma NA/2.5 mL Negative control PBS/2.5 mL MAb c7d11 6-63 PBS/2.5 mL 6-3  PBS/2.5 mL 6-36 PBS/2.5 mL NA = not applicable

Animals injected intraperitonealy (i.p.) with the Negative Control antibody lost weight starting losing significant amounts of weight between Days 5 and 6 and continued to decline until the end of the experiment on Day 9. The maximum mean weight loss of the group was −11.7%. In contrast, animals injected with positive control human convalescent plasma maintained weight within −3.2% of their weight on Day 0 indicating this plasma protected against disease manifested by weight loss (FIG. 34A).

Groups of six animals were injected i.p. with 10, 5, or 1 mg/kg of monoclonal antibody 6-63 diluted in PBS. All groups maintained their weight at or above starting weight indicating the antibody protected against disease resulting weight loss (FIG. 34B).

Groups of six animals were injected i.p. with 10, 5, or 1 mg/kg of monoclonal antibody 6-3 diluted in PBS. The 1 and 10 mg/kg groups maintained their weight at or above starting weight at all time points. The 5 mg/kg group weight dipped slightly below the convalescent control on Days 7-9 but clearly was different from the Negative Control antibody. Together, these data indicate the antibody decreased weight loss associated with disease (FIG. 34C).

Groups of six animals were injected i.p. with 10, 5, or 1 mg/kg of monoclonal antibody 6-36 diluted in PBS. The 10 and 5 mg/kg groups maintained their weight at levels similar to the positive control at all time points. The 1 mg/kg group weight dropped significantly similar to the Negative Control. These data indicate antibody 6-36 at 1 mg/kg is insufficient to provide benefit, but a 5-fold or greater dose is adequate to reduce disease as determined by weight loss (FIG. 34D).

FIG. 34E shows data from the variant antibodies grouped by dose. FIG. 34F shows graphs of percent weight change for antibodies 6-3, 6-63, and 1-20.

In wild type hamsters, virus is typically cleared by Day 7. However, in the cyclophosphamide model, viral levels are not suppressed unless there is intervention (e.g. protective antibodies administered) or the cyclophosphamide is discontinued to allow immune response and clearance. In this experiment the positive control human convalescent serum eliminated virus from the lungs from all except one hamster. In contrast, all but one of the hamsters injected with negative control antibody still had infectious virus in the lungs. Interestingly, hamsters prophylactically treated (24 hour previous to exposure) with any of the three antibodies at the highest dose (10 mg/kg) had infectious virus in the lungs of at least half the animals assessed 9 days later. Paradoxically, 6-63 and 6-3 at the lower doses (5 and 1 mg/kg) had animals with relatively less infectious virus in the lungs. 4 of 6 animals injected with 1-20 at 5 mg/kg dose animals had no detectable virus in the lungs. When the doses of that antibody was reduced to 1 mg/kg, all but one animal had infectious virus. Data is seen in FIGS. 34G-34H.

Lung pathology inflammation and edema scores from three animals were added per group and plotted (FIG. 34I). These were the same lungs used to score ISH. The convalescent sera positive control median score was 2 and the negative control was 4. The only groups with a median score lower than the negative control group were 1 and 5 mg/kg 6-63, 10 and 5 mg/kg 6-3, and 5 mg/kg 1-20. The highest median pathology scores were the 1 and 10 mg/kg 1-20 groups. The lowest median pathology score was the 5 mg/kg 6-63 group.

Example 9. SARS-CoV-2 Membrane Protein Panning

Variant SARS-CoV-2 antibodies targeting the membrane protein were generated and panned similar to Example 4.

An exemplary construct is seen in FIG. 35. The membrane protein variants were assayed for binding affinity to SARS-CoV-2 membrane protein (data not shown). The membrane protein variants bound in the picomolar and nanomolar range and did not bind to GFP fusion protein as seen in FIGS. 36A-36D.

ELISA assays were performed. Briefly, 1 ug/ml antigen immobilized on Nunc Maxisorp plate. 0.01-333 nM of the antibodies were added to the plate. The secondary antibody used was anti-human Fc-HRP secondary. The data is seen in Tables 16A-16B and FIGS. 37A-37B.

TABLE 16A 9-1 10-55 10-16 10-15 10-28 10-27 10-20 Trastuzumab [Ab] M- M- M- M- M- M- M- M- (nM) GFP BSA GFP BSA GFP BSA GFP BSA GFP BSA GFP BSA GFP BSA GFP BSA 333.33 1.19 0.39 1.05 0.28 1.10 0.38 0.82 0.52 0.94 0.32 0.87 0.23 0.62 0.37 0.14 0.08 111.11 1.13 0.38 0.95 0.40 1.02 0.46 0.53 0.33 0.97 0.35 0.81 0.23 0.71 0.40 0.08 0.06 37.04 1.10 0.46 0.91 0.39 1.02 0.52 0.31 0.20 0.84 0.48 0.75 0.28 0.71 0.36 0.06 0.05 12.35 0.90 0.45 0.75 0.32 0.87 0.49 0.15 0.10 0.83 0.47 0.83 0.34 0.62 0.32 0.05 0.04 4.12 0.80 0.40 0.58 0.20 0.93 0.40 0.09 0.06 0.55 0.35 0.63 0.30 0.69 0.22 0.05 0.04 1.37 0.61 0.27 0.30 0.10 0.59 0.24 0.06 0.06 0.41 0.22 0.52 0.22 0.44 0.14 0.05 0.04 0.46 0.33 0.14 0.16 0.07 0.29 0.13 0.05 0.05 0.21 0.12 0.30 0.12 0.24 0.08 0.04 0.04 0.15 0.16 0.08 0.07 0.05 0.15 0.08 0.05 0.04 0.10 0.07 0.15 0.07 0.12 0.05 0.04 0.04 0.05 0.11 0.07 0.06 0.04 0.08 0.05 0.04 0.04 0.06 0.05 0.08 0.05 0.07 0.04 0.04 0.04 0.02 0.10 0.04 0.05 0.04 0.05 0.04 0.04 0.04 0.05 0.04 0.05 0.04 0.05 0.04 0.04 0.04 0.01 0.05 0.04 0.09 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.05 0.04 0.04 0.04

TABLE 16B [Ab] (nM) 9-11 10-55 10-16 10-15 10-28 10-27 10-20 Trastuzumab 333.33 3.04 3.74 2.88 1.57 2.94 3.87 1.67 1.69 111.11 2.96 2.39 2.22 1.61 2.77 3.52 1.79 1.49 37.04 2.39 2.36 1.98 1.57 1.74 2.71 1.96 1.31 12.35 2.02 2.39 1.77 1.47 1.76 2.46 1.94 1.17 4.12 2.02 2.89 2.35 1.49 1.59 2.11 3.07 1.13 1.37 2.27 2.95 2.47 1.06 1.90 2.40 3.21 1.13 0.46 2.38 2.23 2.20 1.06 1.79 2.42 3.21 1.08 0.15 1.97 1.44 1.82 1.09 1.47 2.09 2.27 1.01 0.05 1.72 1.23 1.51 1.07 1.23 1.54 1.51 1.04 0.02 2.16 1.06 1.20 0.97 1.11 1.24 1.21 1.03 0.01 1.12 2.24 1.15 1.07 1.08 1.12 1.09 1.04

FACS titration was also performed. Data is seen in Table 16C and FIGS. 38A-38J.

[IgG] ProSci ProSci ProteinTech nM 9-11 10-55 10-16 10-15 10-28 10-27 10-20 Sars-Cov2-M1 Sars-Cov2-M1 Sars-Cov2-M1 100 2.08 2.80 3.07 2.72 13.46 1.49 3.23 5.60 3.51 6.07 33.333 2.58 4.10 4.61 2.27 9.80 1.47 4.10 3.72 2.82 4.85 11.111 2.96 3.43 3.22 2.05 5.87 2.09 3.58 2.83 2.20 4.79 3.704 3.63 2.46 2.31 1.77 3.05 1.81 3.00 2.05 1.89 3.13 1.235 3.37 1.48 1.95 1.55 2.54 2.68 2.62 1.94 2.92 1.89 0.412 2.38 1.31 1.52 1.36 1.99 1.70 2.13 1.83 2.00 1.64 0.137 2.00 1.37 1.27 1.36 1.58 1.26 1.45 1.91 1.81 1.48 0.046 1.61 1.38 1.31 1.76 1.60 1.37 1.49 1.61 1.63 1.59

Data for antibodies having improved affinity and binding is seen in Table 16D and FIGS. 39A-39B.

TABLE 16D MFI Variant Expressing MFI Parent MFI Ratio 10-13 31498 3565.5 8.83 9-1 35223 4299 8.19 10-18 8516 1056 8.06 10-45 18004 2691 6.69 10-26 8204.5 1577 5.20 10-22 14691 3285 4.47 10-48 11680 2838.5 4.11 10-52 2165 527 4.11 10-40 14490 3833 3.78 9-8 8705.5 2318 3.76 ProteinTech 7390 2007 3.68 Sars-Cov2-M1 10-38 8777 2554 3.44 10-61 19571 6131.5 3.19 9-9 4843 1541 3.14 10-08 18743 5964 3.14 10-24 4735.5 1554 3.05 9-4 26899 8829.5 3.05 10-10 38014 12508.5 3.04 10-58 12538 4421 2.84 10-35 3279 1179 2.78 10-07 2631 1005 2.62 10-46 14703 5650 2.60 10-23 24789 10112 2.45 10-37 6580.5 2727 2.41 10-34 4416 1837 2.40 10-27 18804 8030 2.34 10-59 12781 5560 2.30 10-33 4429.5 1935 2.29 10-14 5189 2346 2.21 10-21 28963 13223.5 2.19 10-49 6702 3071.5 2.18 10-39 12127.5 5731 2.12 10-04 5561 2638 2.11 10-28 18309 8872.5 2.06 10-53 5940.5 2920 2.03 10-12 11043 5451 2.03 9-5 79505 40263 1.97 10-25 2231 1136 1.96 9-7 60739 31110 1.95 10-03 35529 19063.5 1.86 10-32 25569 13832 1.85 10-20 29454 16158 1.82 10-36 31774 17549 1.81 10-57 29745 16648 1.79 10-54 89446 50215 1.78 10-41 8910 5090.5 1.75 10-42 70764 40576 1.74 10-50 423775 246262 1.72 10-31 1460 880.5 1.66  9-11 141975 87474 1.62 10-47 70545.5 43576.5 1.62 10-09 41228 25611.5 1.61 9-3 45285 28206 1.61 10-05 70182 44064 1.59 10-17 69948 44097.5 1.59 10-30 37623.5 23973 1.57 10-11 43592 27861 1.56 10-43 16903.5 10901 1.55 10-19 74841 48651 1.54  9-10 123764 81408 1.52 10-29 6272 4230.5 1.48 10-51 91221 61911 1.47 9-6 669267 454499.5 1.47 10-44 19771 13568 1.46 10-56 11075.5 7946 1.39 9-2 936 721 1.30 Stained 208 164 1.27 Control R 10-02 413 331 1.25 10-55 1951.5 1585 1.23 Stained 198 166 1.19 Control H 10-60 100191.5 87809 1.14 10-01 958 884 1.08 10-06 1375 1273 1.08 10-15 1912 1777 1.08 10-16 910 866 1.05

The membrane protein antibodies were assayed in flow titration assay for pool and single pool HEK. Data is seen in FIGS. 40A-40C. Of the membrane protein antibodies, 9-11, 10-13, 9-28, 10-18, 10-48, and 10-55 exhibited improved characteristics (FIG. 40D).

Example 10. VSV-Pseudotype Neutralization Analysis of Antibodies for SARS-CoV-2 B.135 (South African Strain)

Antibodies described herein were tested in a VSV-pseudotype neutralization assay for SARS-CoV-2 B.135 (South African strain).

Briefly, aerial semi-log dilutions of all test antibodies (TA) and control were prepared and mixed with the VSV-pseudotype virus in a 1:1 ratio for 1 h at RT followed by incubation over Vero cells (ATCC® CCL-81™) seeded at 60,000 cells per well at 37° C. The cells were lysed the following day and luciferase activity was measured to assess the potency of each TA to block viral entry into the Vero cells. All samples will be run in triplicate. Data analysis is conducted using XLFit and Graphpad Prism. The testing concentrations and plate plan are seen in Table 17.

TABLE 17 Testing Concentrations and Plate Plan Target Stock conc/ Samples (mg/mL) dilution In plate concentration 1 6-63 6.39 100 ug/mL 50.00 ug/mL 2 6-3  10.05 100 ug/mL 50.00 ug/mL 3 1-12 2.24 100 ug/mL 50.00 ug/mL 4 mouse 1 1:25 1:50 pAb

Data is seen in FIGS. 41A-41B. FIG. 41A illustrates positive control pAb has an NT50 of 1:14,993 dilution as expected. FIG. 41B illustrates antibodies 6-63 and 6-3 neutralize VSV-SARS B.135 strain with IC50s of ˜3.07 ug/mL and 0.143 ug/mL, respectively. Antibody 1-12 failed to neutralize VSV-SARS B.135 strain.

Example 11. VSV-Pseudotype Neutralization Analysis of Antibodies for SARS-CoV-2 D614G Variant

Antibodies described herein were tested in a VSV-pseudotype neutralization assay for SARS-CoV-2 SARS CoV-2 S D614G variant.

Briefly, serial semi-log dilutions of all test antibodies (TA) and control were prepared and mixed with the VSV-pseudotype virus in a 1:1 ratio for 1 h at RT followed by incubation over Vero cells (ATCC® CCL-81™) seeded at 60,000 cells per well at 37° C. The cells were lysed the following day and luciferase activity was measured to assess the potency of each TA to block viral entry into the Vero cells. All samples will be run in triplicate. Data analysis is conducted using XLFit and Graphpad Prism.

Data is seen in FIGS. 42A-42D. FIG. 42A shows the positive control.

Example 13. Antibody Cocktails for Treating SARS-CoV-2 in Syrian Hamsters

This Example demonstrates pre- and post-exposure efficacy of antibody cocktails in Syrian hamsters.

Methods

In this study the hamsters were transiently immunosuppressed using cyclophosphamide. As a strategy to de-risk selecting viruses with neutralization escape mutations a cocktail of a nanobody (nAb) and a monoclonal antibody (MAb) known to bind different spike protein epitopes were combined and used. The combined dose was 20 mg/Kg in this proof-of-concept experiment. The cocktail consisted of 10 mg/Kg of VHH nanobody 6-63 and 10 mg/Kg of monoclonal antibody 1-20. An equal number of male and female animals were used in each group.

Seventy-eight hamsters were used for this experiment according to Table 18. On Day 0, animals were exposed via intranasal (IN) instillation to 1,000 pfu of SARS-CoV-2 virus in 50 μL volume. The volume was distributed between both nares. To transiently immunosuppress, all animals were treated with cyclophosphamide starting on Day −3 (140 mg/kg dose) followed by additional doses (100 mg/kg) on Days 1, 5, and 9.

On the indicated day post exposure, MAb/nAb cocktail or c7D11 was administered via the intraperitoneal (IP) route. On Day 0 blood samples were collected from Group I for hematology to confirm immunosuppression. Group I was also the control for any adverse effects of cyclophosphamide treatment on the hamsters. Clinical scores and individual animal weights were recorded daily. Pharyngeal swabs and other key events were measured. Animals in Groups A-I were euthanized on day 14 and lungs were collected for virology and pathology. Group J animals were used for a serial pathology component of this study. Two animals from Group J (2 male and 2 female) were euthanized starting on Day 1 and then each day up to and including Day 6.

TABLE 18 Experimental design Number of Virus Hamsters (Pain Exposure^(a) Treatment Group Category) (Day 0) Treatment Day A 6 (3 male, 3 SARS CoV-2 Cocktail^(b) −1 female) (D) 20 mg/Kg B 6 (3 male, 3 Cocktail^(b) +1 female) (D) 20 mg/Kg C 6 (3 male, 3 Cocktail^(b) +2 female) (D) 20 mg/Kg D 6 (3 male, 3 Cocktail^(b) +3 female) (D) 20 mg/Kg E 6 (3 male, 3 Cocktail^(b) +4 female) (D) 20 mg/Kg F 6 (3 male, 3 Cocktail^(b) +5 female) (D) 20 mg/Kg G 6 (3 male, 3 Cocktail^(b) +6 female) (E) 20 mg/Kg H 6 (3 male, 3 Neg IgG +1 female) (E) control I 6 (3 male, 3 No virus none Cyclophospha- female) (C) mide control J 24 (12 male, SARS CoV-2 none No treatment- 12 female) (E) pathology control^(d) 78 Syrian hamsters ^(a)challenge with 1,000 pfu of virus in 50 microliter volume ^(b)cocktail = 6-63 combined with 1-20 1:1 w/v delivered 2.5 mL per animal by i.p. route ^(c) negative control 20 mg/kg ^(d)Two animals (2 male and 2 female) from Group J were euthanized for pathology/virology on Days 1, 2, 3, 4, 5, 6

Results

Cyclophosphamide Treatment in Uninfected Animals does not Result in Weight Loss.

Control animals (CYP Controls, Group I), that were treated with CYP but not challenged gained weight overtime.

Negative Control Antibody c7D11 at 20 mg/kg, Group H, does not Protect Against Disease Associated Weight Loss.

Hamsters in Group H lost weight starting on Day 6 (FIG. 43A). Weight loss continued until Day 10 when it leveled off Animals were still below 10% of their starting weight on the last day of the experiment (Day 14).

The Cocktail Administered One Day Prior to Exposure Protected Against Weight Loss.

Hamsters in Group A maintained their weight and stayed within 1% of starting weight (FIG. 43A). This confirmed that treatment with neutralizing antibodies before exposure was sufficient to protect against significant weight loss.

Post-Exposure Treatment of CYP Hamster Model of COVID19 Produces Variable Weight Loss Effects/Patterns.

A onetime treatment of a cocktail containing 1-20 and 6-63 at final dose of 20 mg/Kg was administered on Days 1 (B), 2 (C), 3 (D), 4 (E), 5 (F), and 6 (G). The percent weight change relative to Day 0 are shown in FIG. 43A. Arrows and dotted vertical lines indicate the day of treatment specific for the treatment regimen being compared. The same data is shown collectively in FIG. 43B. Note that there were two animals in Group B (Day 1) that dropped weight a typically during the experiment and one animal succumbed on Day 12. That animal had a necrotic/hemorrhaging testicle due to an apparent torsion event and was excluded from analysis. No assignable cause was identified for the second animal so that animal was not excluded from analysis. Statistical analysis was performed to compare both the CYP Control (Group I) and the negative control antibody (c7d11, Group H) to all other groups. The significance between groups at individual timepoints and differences in area under the curve (AOC) were determined. Treatment with the cocktail one day after exposure (Group B) results were confounded by the outlier animal There was not a significant differences in AOC between Group B and Group H suggesting no protection; however, there was also no significant difference in the AOC between Group A and Group I indicating Group B weight loss was not significantly different from the CYP control group that was not exposed. Treatment with the cocktail two days after exposure (Group C) clearly protected. There was significant differences in AOC between Group C and Group H; and no significant difference in the AOC between Group C and Group I. Treatment after three days (Day 3 Group D) did not result in a significant difference in AOC between Group D and H. However, treatment on day 4 or 5 after exposure (Groups E and F, respectively) did significant reduce the AOC relative to Group H. Treatment on day 6 (Group G) was similar to treatment on day 3 where no significant difference in AOR between Group G and H. Although there was no significance in the AOC for the Day 6 treatment group, the last three timepoints weight loss was significantly less than the negative control group. Interestingly, groups administered antibody on Days 3, 4, 5, or 6 started to gain weight starting on Day 9 whereas the negative control antibody treated animals did not. This suggests that there was a benefit of all cocktail treatment even at as late as 6 days post-exposure.

Infectious Virus in Lungs (Day 14/15).

In wild type hamsters, virus is typically cleared by Day 7. However, in the cyclophosphamide model virus is not suppressed unless there is intervention (e.g. protective antibodies administered) or the cyclophosphamide is discontinued to allow immune response and clearance. Here, our controls demonstrate that unexposed hamsters were negative for virus (Cyp Cont), whereas all hamsters exposed to virus and treated with an off-target monoclonal antibody (Neg Cont) had more than 10,000 pfu of virus per gram of lung tissue. Most of the hamsters treated with the Cocktail one day prior or one day post virus exposure had detectable levels of virus in lung samples collected on Day 14 (Groups A and B). However, almost all of the hamsters treated with antibody >2 day after exposure had undetectable levels of antibody in their lungs. There was only a single animal exception in the Day 2, 3, 4 and 6 treated groups. All of the hamsters treated on Day 5 had lungs that were free of infectious virus. See FIG. 43C.

Sequential Sampling.

Hamsters immunosuppressed and exposed to virus on Day 0 were sampled overtime to monitor the infection. Infectious virus was detected in the lungs of 3 of 4 hamsters on Day 1. Levels of infectious virus then increased more than 4 logs by Day 2. Levels of virus then leveled off and stayed between 7-9 log 10 through the last sampling timepoint (Day 6) analyzed to-date. Thus, animals administered the cocktail after Day 1 likely had very high levels of infectious virus present in their lungs before treatment with the antibody. See FIG. 43D.

Conclusion

The data demonstrates that when administered at or before Day 2 relative to virus exposure, the combination of antibody and nanobody at 20 mg/kg was sufficient to provide convincing benefit as determined by the disease parameters analyzed. When treated after Day 2, animals still developed weight loss but recovered in approximately 4 days. Two weeks after virus exposure, more infectious virus was detected in the lungs of hamsters receiving antibody early (Day −1 or 1) than day 2 or later. Day 2 (or later) treatment of exposed animals occurred at a time when viral burden in the lungs was already remarkably high. CYP, by itself, does not induce weight loss or clinical signs of disease.

Example 14. Immunity Conferred by SARS-CoV-2 and ACE2 Antibodies

Antibodies described in Examples 4-6 are used to confer immunity in a subject. A subject is passively immunized with a SARS-CoV-2 or ACE2 antibody. The subject is then exposed to SARS-CoV-2 after immunization with the SARS-CoV-2 or ACE2 antibody. Exposure can be within a few days or within a few months. The subject can also receive the SARS-CoV-2 or ACE2 antibody immediately following exposure with SARS-CoV-2. Although the subject is exposed to SARS-CoV-2, the subject has developed an immunity against SARS-CoV-2 and infection is prevented.

Example 15. Sequences

Tables 19-41 show exemplary sequences for CDRH1-H3 and CDRL1-L3 as well as variant heavy chains and variant light chains for the SARS-CoV-2 and ACE2 variants.

TABLE 19 ACE2 VHH Variable Heavy Chain CDRs SEQ SEQ SEQ ID ID ID Variant NO CDRH1 NO CDRH2 NO CDRH3 4-1 1 RTFSDDTMG 51 GGISWSGGNTYYA 101 CATDPPLFW 4-2 2 RTFGDYIMG 52 AAINWSAGYTAYA 102 CARASPNTGWHFDRW 4-3 3 RTFSDDAMG 53 AAINWSGGTTRYA 103 CATDPPLFW 4-4 4 RTFGDYIMG 54 AAINWIAGYTADA 104 CAEPSPNTGWHFDHW 4-5 5 RTFGDDTMG 55 AAINWSGGNTYYA 105 CATDPPLFW 4-6 6 RTFGDDTMG 56 AAINWTGGYTPYA 106 CATDPPLFW 4-7 7 RTFGDYIMG 57 AAINWSGGYTAYA 107 CATASPNTGWHFDHW 4-8 8 RTFGDYIMG 58 GGINWSGGYTYYA 108 CATDPPLFW 4-9 9 RTFGDYIMG 59 AAINWSGGYTHYA 109 CATDPPLFW 4-10 10 RTFSDDTMG 60 AAIHWSGSSTRYA 110 CATDPPLFW 4-11 11 RTFGDYAMG 61 APINWSGGSTYYA 111 CATDPPLFW 4-12 12 RTFGDDTMG 62 AAINWSGGNTPYA 112 CATDPPLFW 4-13 13 RTFGDDTMG 63 AAINWSGDNTHYA 113 CATDPPLFW 4-14 14 RTFSDDTMG 64 AAINWSGGTTRYA 114 CATDPPLFW 4-15 15 RTFSDDTMG 65 AAINWSGDSTYYA 115 CATDPPLFW 4-16 16 RTFSDYTMG 66 AAINWSGGYTYYA 116 CATDPPLFW 4-17 17 RTFGDDTMG 67 AAINWSGGNTDYA 117 CATDPPLFW 4-18 18 RTFGDYIMG 68 AAINWSGGYTPYA 118 CATDPPLFW 4-19 19 RTFSDDTMG 69 AAINWSGGSTYYA 119 CATDPPLFW 4-20 20 RTFGDDIMG 70 AAIHWSAGYTRYA 120 CATDPPLFWGHVDLW 4-21 21 RTFSDDTMG 71 AGMTWSGSSTFYA 121 CATDPPLFW 4-22 22 RTFGDYIMG 72 AAINWSGDNTHYA 122 CATDPPLFW 4-23 23 RTFSDDAMG 73 AGISWNGGSIYYA 123 CATDPPLFW 4-24 24 RTFSDYTMG 74 AAINWSGGTTYYA 124 CATDPPLFW 4-25 25 GTFSRYAMG 75 SAVDSGGSTYYA 125 CAASPSLRSAWQW 4-26 26 RTFSDDTMG 76 AAVNWSGGSTYYA 126 CATDPPLFW 4-27 27 RTFGDYIMG 77 AAINWSAGYTAYA 127 CARATPNTGWHFDHW 4-28 28 RTFGDDTMG 78 AAINWNGGNTHYA 128 CATDPPLFW 4-29 29 RTFGDDTMG 79 AAINWSGGYTYYA 129 CATDPPLFW 4-30 30 RTFGDYTMG 80 AAINWTGGYTYYA 130 CATDPPLFW 4-31 31 RTFGDYIMG 81 AAINWSAGYTAYA 131 CATASPNTGWHFDHW 4-32 32 FTFDDYEMG 82 AAISWRGGTTYYA 132 CAADRRGLASTRAGDYDW 4-33 33 FTFSRHDMG 83 AGINWESGSTNYA 133 CAADRGVYGGRWYRTSQY TW 4-34 34 RTFGDYIMG 84 AAINWSADYTAYA 134 CATDPPLFCWHFDHW 4-35 35 QLANFASYAMG 85 AAITRSGSSTVYA 135 CATTMNPNPRW 4-36 36 RTFGDYIMG 86 AAINWSAGYTAYA 136 CATAPPLFCWHFDHW 4-37 37 RTFGDYGMG 87 ATINWSGALTHYA 137 CATLPFYDFWSGYYTGYYY MDVW 4-38 38 RTFSDDTMG 88 AAITWSGGRTRYA 138 CATDRPLFW 4-39 39 RTFSNAAMG 89 ARILWTGASRNYA 139 CATTENPNPRW 4-40 40 RTFSDDTMG 90 AGINWSGNGVYYA 140 CATDPPLFW 4-41 41 RTFGDYIMG 91 AAINWSGGTTPYA 141 CATDPPLFCCHVDLW 4-42 42 RTFGDDTMG 92 AAINWSGGYTPYA 142 CATDPPLFWGHVDLW 4-43 43 RTFSDDTMG 93 AAINWSGGSTDYA 143 CATDPPLFW 4-44 44 RTFGDYIMG 94 AAINWSAGYTAYA 144 CATARPNTGWHFDHW 4-45 45 RTFSDDAMG 95 AAINWSGGSTRYA 145 CATDPPLFW 4-46 46 RTFGDYIMG 96 AAINWSAGYTPYA 146 CATDPPLFWGHVDLW 4-47 47 FTFGDYVMG 97 AAINWNAGYTAYA 147 CAKASPNTGWHFDHW 4-48 48 RTFSDDAMG 98 GRINWSGGNTYYA 148 CATDPPLFW 4-49 49 RTFGDYIMG 99 AAINWSAGYTAYA 149 CARASPNTGWHFDHW 4-50 50 GTFSNSGMG 100 AVVNWSGRRTYYA 150 CAVPWMDYNRRDW

TABLE 20 SARS-CoV-2 S1 Variable Heavy Chain CDRs SEQ SEQ SEQ ID ID ID Variant NO CDRH1 NO CDRH2 NO CDRH3 2-1 151 FTFSNYATD 166 SIISGSGGATYYA 181 CAKGGYCSSDTCWWEYWLDPW 2-2 152 FTFSRHAMN 167 SGISGSGDETYYA 182 CARDLPASYYDSSGYYWHNGMDVW 2-3 153 FTFSDFAMA 168 SAISGSGDITYYA 183 CAREADCLPSPWYLDLW 2-4 154 FTFSDFAMA 169 SAITGTGDITYYA 184 CAREADGLHSPW 2-5 155 FTFSDFAMA 170 SAISGSGDITYYA 185 CAREADGLHSPWHFDLW 2-6 156 FTFSDFAMA 171 SAISGSGDITYYA 186 CAREADGLHSPWHFDLW 2-7 157 FTFSDFAMA 172 SAITGSGDITYYA 187 CAREADGLHSPWHFDLW 2-8 158 FTFSDFAMA 173 SAISGSGDITYYA 188 CAREADGLHSPWHFDLW 2-9 159 FTFPRYAMS 174 STISGSGSTTYYA 189 CARLIDAFDIW 2-10 160 FTFSAFAMG 175 SAITASGDITYYA 190 CARQSDGLPSPWHFDLG 2-11 161 FTFSNYPMN 176 STISGSGGNTFYA 191 CVRHDEYSFDYW 2-12 162 FTFSDYPMN 177 STISGSGGITFYA 192 CVRHDEYSFDYW 2-13 163 FTFSDYPMN 178 SAISGSGDNTYYA 193 CVRHDEYSFDYW 2-14 164 FTFSDYPMN 179 SAITGSGDITYYA 194 CVRHDEYSFDYW 2-15 165 FTFSDYPMN 180 STISGSGGITFYA 195 CVRHDEYSFDYW

TABLE 21 SARS-CoV-2 S1 Variable Light Chain CDRs SEQ SEQ SEQ ID ID ID Variant NO CDRL1 NO CDRL2 NO CDRL3 2-1 196 RASQSIHRFLN 211 AASNLHS 226 CQQSYGLPPTF 2-2 197 RASQTINTYLN 212 SASTLQS 227 CQQSYSTFTF 2-3 198 RASQNIHTYLN 213 AASTFAK 228 CQQSYSAPPYTF 2-4 199 RA5Q5IDTYLN 214 AASALAS 229 CQQSYSAPPYTF 2-5 200 RASQSIHTYLN 215 AASALAS 230 CQQSYSAPPYTF 2-6 201 RASQSIDTYLN 216 AASALAS 231 CQQSYSAPPYTF 2-7 202 RASQSIDTYLN 217 AASALAS 232 CQQSYSAPPYTF 2-8 203 RASQSIDTYLN 218 AASALAS 233 CQQSYSAPPYTF 2-9 204 RASQRIGTYLN 219 AASNLEG 234 CQQNYSTTWTF 2-10 205 RASQSIHISLN 220 LASPLAS 235 CQQSYSAPPYTF 2-11 206 RASQSIGNYLN 221 GVSSLQS 236 CQQSHSAPLTF 2-12 207 RASQSIDNYLN 222 GVSALQS 237 CQQSHSAPPYFF 2-13 208 RASQSIDTYLN 223 GASALES 238 CQQSHSAPPYFF 2-14 209 RASQSIDTYLN 224 GVSALQS 239 CQQSYSAPPYFF 2-15 210 RASQSIDNYLN 225 GVSALQS 240 CQQSHSAPLTF

TABLE 22 ACE2 Variable Heavy Chain CDRs SEQ SEQ SEQ ID ID ID Variant NO CDRH1 NO CDRH2 NO CDRH3 3-1 241 FMFGNYAMS 256 AAISGSGGSTYYA 271 CAKDRGYSSSWYGGFDYW 3-2 242 FTFRSHAMN 257 SAISGSGGSTNYA 272 CARGLKFLEWLPSAFDIW 3-3 243 FTFRNYAMA 258 SGISGSGGTTYYG 273 CARGTRFLEWSLPLDVW 3-4 244 FTFRNHAMA 259 SGISGSGGTTYYG 274 CARGTRFLQWSLPLDVW 3-5 245 FTITNYAMS 260 SGISGSGAGTYYA 275 CARHAWWKGAGFFDHW 3-6 246 FTIPNYAMS 261 SGISGAGASTYYA 276 CARHTWWKGAGFFDHW 3-7 247 FTIPNYAMS 262 SGISGSGASTYYA 277 CARHTWWKGAGFFDHW 3-8 248 FTITNYAMS 263 SGISGSGASTYYA 278 CARHTWWKGAGFFDHW 3-9 249 FTITNYAMS 264 SGISGSGAGTYYA 279 CARHTWWKGAGFFDHW 3-10 250 FTFRSHAMS 265 SSISGGGASTYYA 280 CARVKYLTTSSGWPRPYFDNW 3-11 251 FTIRNYAMS 266 SSISGGGASTYYA 281 CARVKYLTTSSGWPRPYFDNW 3-12 252 FTFRSHAMS 267 SSISGGGASTYYA 282 CARVKYLTTSSGWPRPYFDNW 3-13 253 FTFRSHAMS 268 SSISGGGASTYYA 283 CARVKYLTTSSGWPRPYFDNW 3-14 254 FTFRSYAMS 269 SSISGGGASTYYA 284 CARVKYLTTSSGWPRPYFDNW 3-15 255 FTFSAYSMS 270 SAISGSGGSRYYA 285 CGRSKWPQANGAFDIW

TABLE 23 ACE2 Variable Light Chain CDRs SEQ SEQ SEQ ID ID ID Name NO CDRL1 NO CDRL2 NO CDRL3 3-1 286 RASQTIYSYLN 301 ATSTLQG 316 CQHRGTF 3-2 287 RTSQSINTYLN 302 GASNVQS 317 CQQSYRIPRTF 3-3 288 RASRSISRYLN 303 AASSLQA 318 CQQSYSSLLTF 3-4 289 RASRSIRRYLN 304 ASSSLQA 319 CQQSYSTLLTF 3-5 290 RASQSIGRYLN 305 AASSLKS 320 CQQSYSLPRTF 3-6 291 RASQSIGKYLN 306 ASSSLQS 321 CQQSYSPPFTF 3-7 292 RASQSIGRYLN 307 ASSSLQS 322 CQQSYSLPRTF 3-8 293 RASQSIGRYLN 308 AASSLKS 323 CQQSYSLPLTF 3-9 294 RASQSIGRYLN 309 AASSLKS 324 CQQSYSLPRTF 3-10 295 RASQSIRKYLN 310 ASSTLQR 325 CQQSLSTPFTF 3-11 296 RASQSIGKYLN 311 ASSTLQR 326 CQQSLSPPFTF 3-12 297 RASQSIGKYLN 312 ASSTLQR 327 CQQSLSTPFTF 3-13 298 RASQSIGKYLN 313 ASSTLQR 328 CQQSFSPPFTF 3-14 299 RASQSIGKYLN 314 ASSTLQR 329 CQQSFSTPFTF 3-15 300 RASQNIKTYLN 315 AASKLQS 330 CQQSYSTSPTF

TABLE 24 SARS-CoV-2 S1 Variable Heavy Chain CDRs SEQ SEQ SEQ ID ID ID Name NO CDRH1 NO CDRH2 NO CDRH3  2-1 331 FTFSNYATD 358 SIISGSGGATYYA 385 CAKGGYCSSDTCWWEYWLDPW 2-10 332 FTFSAFAMG 359 SAITASGDITYYA 386 CARQSDGLPSPWHFDLG 2-5 333 FTFSDFAMA 360 SAISGSGDITYYA 387 CAREADGLHSPWHFDLW 2-2 334 FTFSRHAMN 361 SGISGSGDETYYA 388 CARDLPASYYDSSGYYWHNGMDVW 2-4 335 FTFSDFAMA 362 SAISGSGDITYYA 389 CAREADGLHSPWHFDLW 2-6 336 FTFSNYPMN 363 STISGSGGNTFYA 390 CVRHDEYSFDYW 2-11 337 FTFSDFAMA 364 SAITGSGDITYYA 391 CAREADGLHSPWHFDLW 2-12 338 FTFSDYPMN 365 STISGSGGITFYA 392 CVRHDEYSFDYW 2-13 339 FTFSDYPMN 366 SAISGSGDNTYYA 393 CVRHDEYSFDYW 2-14 340 FTFSDFAMA 367 SAITGTGDITYYA 394 CAREADGLHSPW 2-7 341 FTFSDYPMN 368 SAITGSGDITYYA 395 CVRHDEYSFDYW 2-8 342 FTFSDFAMA 369 SAISGSGDITYYA 396 CAREADGLHSPWHFDLW 2-15 343 FTFSDFAMA 370 SAISGSGDITYYA 397 CAREADGLHSPWHFDLW 2-9 344 FTFPRYAMS 371 STISGSGSTTYYA 398 CARLIDAFDIW 2-16 345 FTFSSYAMS 372 SVISGSGGSTYYA 399 CAREGYRDYLWYFDLW 2-17 346 FTFSNYAMS 373 SAISGSAGSTYYA 400 CARVRQGLRRTWYYFDYW 2-18 347 FTFSSYAMY 374 SAISGSAGSTYYA 401 CARDTNDFWSGYSIFDPW 2-19 348 FTFSSYTMS 375 SVISGSGGSTYYA 402 CAREGYRDYLWYFDLW 2-2 349 FTFSSYDMS 376 SVISGSGGSTYYA 403 CAKGPLVGWYFDLW 2-21 350 FTFPRYAMS 377 STISGSGSTTYYA 404 CARLIDAFDIW 2-22 351 FTFTTYALS 378 SGISGSGDETYYA 405 CTTGDDFWSGGNWFDPW 2-23 352 FTFSRHAMN 379 SGITGSGDETYYA 406 CARDLPASYYDSSGYYWHNGMDVW 2-24 353 FVFSSYAMS 380 SAISGSGGSSYYA 407 CARVGGGYWYGIDVW 2-25 354 FTLSSYVMS 381 SGISGGGASTYYA 408 CARGYSRNWYPSWFDPW 2-26 355 FTFSTYAMS 382 SSIGGSGSTTYYA 409 CAGGWYLDYW 2-27 356 FTYSNYAMT 383 SAISGSSGSTYYA 410 CASLCIVDPFDIW 2-28 357 FTFSNYPMN 384 STISGSGGNTFYA 411 CVRHDEYSFDYW

TABLE 25 SARS-CoV-2 S1 Variable Light Chain CDRs SEQ SEQ SEQ ID ID ID Name NO CDRL1 NO CDRL2 NO CDRL3 2-1 412 RASQSIHRFLN 439 AASNLHS 466 CQQSYGLPPTF 2-10 413 RASQSIHISLN 440 LASPLAS 467 CQQSYSAPPYTF 2-5 414 RASQSIHTYLN 441 AASALAS 468 CQQSYSAPPYTF 2-2 415 RASQTINTYLN 442 SASTLQS 469 CQQSYSTFTF 2-4 416 RASQSIDTYLN 443 AASALAS 470 CQQSYSAPPYTF 2-6 417 RASQSIGNYLN 444 GVSSLQS 471 CQQSHSAPLTF 2-11 418 RASQSIDTYLN 445 AASALAS 472 CQQSYSAPPYTF 2-12 419 RASQSIDNYLN 446 GVSALQS 473 CQQSHSAPPYFF 2-13 420 RASQSIDTYLN 447 GASALES 474 CQQSHSAPPYFF 2-14 421 RASQSIDTYLN 448 AASALAS 475 CQQSYSAPPYTF 2-7 422 RASQSIDTYLN 449 GVSALQS 476 CQQSYSAPPYFF 2-8 423 RASQSIDTYLN 450 AASALAS 477 CQQSYSAPPYTF 2-15 424 RASQSIDNYLN 451 GVSALQS 478 CQQSHSAPLTF 2-9 425 RASQRIGTYLN 452 AASNLEG 479 CQQNYSTTWTF 2-16 426 TGTSSDVGSYDLVS 453 EGNKRPS 480 CCSYAGSSVVF 2-17 427 TGTSSDVGSSNLVS 454 EGSKRPS 481 CCSYAGSLYVF 2-18 428 TGTSSDIGSYNLVS 455 EGTKRPS 482 CCSYAGSRTYVF 2-19 429 TGTSTDVGSYNLVS 456 EGTKRPS 483 CCSYAGSYTSVVF 2-2 430 TGTSSNVGSYNLVS 457 EGTKRPS 484 CCSYAGSSSFVVF 2-21 431 RASQSIHTYLN 458 AASALAS 485 CQQSYSAPPYTF 2-22 432 RASQSIHTYLN 459 AASALAS 486 CQQSYSAPPYTF 2-23 433 RASQTINTFLN 460 SASTLQS 487 CQQSYSTFTF 2-24 434 RASQTIRTYLN 461 DASTLQR 488 CQQSYRTPPWTF 2-25 435 RSSQSISSYLN 462 GASRLRS 489 CQQGYSAPWTF 2-26 436 RASQSISGSLN 463 AESRLHS 490 CQQSYSPPQTF 2-27 437 RASRSISTYLN 464 AASNLQG 491 CQQSHSIPRTF 2-28 438 RASQSIHTYLN 465 AASALAS 492 CQQSYSAPPYTF

TABLE 26 SARS-CoV-2 S1 Variant Sequences Variable Heavy Chain SEQ ID Name NO Amino Acid Sequence 2-1 493 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYATDWVRQAPGKGLEWVSIISGS GGATYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGYCSSDTC WWEYWLDPWGQGTLVTVSS 2-10 494 EVQLLESGGGLVQPGGSLRLSCAASGFTFSAFAMGWVRQAPGKGLEWVSAITAS GDITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQSDGLPSPWH FDLGGQGTLVTVSS 2-5 495 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAISGS GDITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPW HFDLWGQGTLVTVSS 2-2 496 EVQLLESGGGLVQPGGSLRLSCAASGFTFSRHAMNWVRQAPGKGLEWVSGISG SGDETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPASYYD SSGYYWHNGMDVWGQGTLVTVSS 2-4 497 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAISGS GDITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPW HFDLWGQGTLVTVSS 2-6 498 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYPMNWVRQAPGKGLEWVSTISGS GGNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRHDEYSFDYW GQGTLVTVSS 2-11 499 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAITGS GDITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPW HFDLWGQGTLVTVSS 2-12 500 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYPMNWVRQAPGKGLEWVSTISGS GGITFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRHDEYSFDYW GQGTLVTVSS 2-13 501 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYPMNWVRQAPGKGLEWVSAISGS GDNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRHDEYSFDYW GQGTLVTVSS 2-14 502 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAITG TGDITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSP WGQGTLVTVSS 2-7 503 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYPMNWVRQAPGKGLEWVSAITGS GDITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRHDEYSFDYW GQGTLVTVSS 2-8 504 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAISGS GDITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPW HFDLWGQGTLVTVSS 2-15 505 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAISGS GDITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPW HFDLWGQGTLVTVSS 2-9 506 EVQLLESGGGLVQPGGSLRLSCAASGFTFPRYAMSWVRQAPGKGLEWVSTISGS GSTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLIDAFDIWGQ GTLVTVSS 2-16 507 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVISGS GGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGYRDYLWY FDLWGQGTLVTVSS 2-17 508 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSAISGS AGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVRQGLRRTW YYFDYWGQGTLVTVSS 2-18 509 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMYWVRQAPGKGLEWVSAISGS AGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDTNDFWSGY SIFDPWGQGTLVTVSS 2-19 510 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVSVISGS GGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGYRDYLWY FDLWGQGTLVTVSS 2-2 511 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSVISGS GGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGPLVGWYFD LWGQGTLVTVSS 2-21 512 EVQLLESGGGLVQPGGSLRLSCAASGFTFPRYAMSWVRQAPGKGLEWVSTISGS GSTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLIDAFDIWGQ GTLVTVSS 2-22 513 EVQLLESGGGLVQPGGSLRLSCAASGFTFTTYALSWVRQAPGKGLEWVSGISGS GDETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTTGDDFWSGGN WFDPWGQGTLVTVSS 2-23 514 EVQLLESGGGLVQPGGSLRLSCAASGFTFSRHAMNWVRQAPGKGLEWVSGITG SGDETYYADSVKGRFTISRDNSKNTLYLQMNSLKAEDTAVYYCARDLPASYYD SSGYYWHNGMDVWGQGTLVTVSS 2-24 515 EVQLLESGGGLVQPGGSLRLSCAASGFVFSSYAMSWVRQAPGKGLEWVSAISGS GGSSYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVGGGYWYGI DVWGQGTLVTVSS 2-25 516 EVQLLESGGGLVQPGGSLRLSCAASGFTLSSYVMSWVRQAPGKGLEWVSGISGG GASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYSRNWYPS WFDPWGQGTLVTVSS 2-26 517 EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMSWVRQAPGKGLEWVSSIGGS GSTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGWYLDYWG QGTLVTVSS 2-27 518 EVQLLGSGGGLVQPGGSLRLSCAASGFTYSNYAMTWVRQAPGKGLEWVSAISG SSGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASLCIVDPFDI WGQGTLVTVSS 2-28 519 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYPMNWVRQAPGKGLEWVSTISGS GGNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRHDEYSFDYW GQGTLVTVSS

TABLE 27 SARS-CoV-2 S1 Variant Sequences Variable Light Chain SEQ ID Name NO Amino Acid Sequence 2-1 520 DIQMTQSPSSLSASVGDRVTITCRASQSIHRFLNWYQQKPGKAPKLLIYAASNLHS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYGLPP-TFGQGTKVEIK 2-10 521 DIQMTQSPSSLSASVGDRVTITCRASQSIHISLNWYQQKPGKAPKLLIYLASPLASG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-5 522 DIQMTQSPSSLSASVGDRVTITCRASQSIHTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-2 523 DIQMTQSPSSLSASVGDRVTITCRASQTINTYLNWYQQKPGKAPKLLIYSASTLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTFTFGQGTKVEIK 2-4 524 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-6 525 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-11 526 DIQMTQSPSSLSASVGDRVTITCRASQSIGNYLNWYQQKPGKAPKLLIYGVSSLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSAPLTFGQGTKVEIK 2-12 527 DIQMTQSPSSLSASVGDRVTITCRASQSIDNYLNWYQQKPGKAPKLLIYGVSALQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSAPPYFFGQGTKVEIK 2-13 528 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYGASALES GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSAPPYFFGQGTKVEIK 2-14 529 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYGVSALQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYFFGQGTKVEIK 2-7 530 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-8 531 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-15 532 DIQMTQSPSSLSASVGDRVTITCRASQSIDNYLNWYQQKPGKAPKLLIYGVSALQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSAPLTFGQGTKVEIK 2-9 533 DIQMTQSPSSLSASVGDRVTITCRASQRIGTYLNWYQQKPGKAPKLLIYAASNLE GGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYSTTWTFGQGTKVEIK 2-16 534 DIQMTQSPSSLSASVGDRVTITCTGTSSDVGSYDLVSWYQQKPGKAPKLLIYEGN KRPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSSVVFGQGTKVEIK 2-17 535 DIQMTQSPSSLSASVGDRVTITCTGTSSDVGSSNLVSWYQQKPGKAPKLLIYEGSK RPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSLYVFGQGTKVEIK 2-18 536 DIQMTQSPSSLSASVGDRVTITCTGTSSDIGSYNLVSWYQQKPGKAPKLLIYEGTK RPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSRTYVFGQGTKVEIK 2-19 537 DIQMTQSPSSLSASVGDRVTITCTGTSTDVGSYNLVSWYQQKPGKAPKLLIYEGT KRPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSYTSVVFGQGTKVEIK 2-2 538 DIQMTQSPSSLSASVGDRVTITCTGTSSNVGSYNLVSWYQQKPGKAPKLLIYEGT KRPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSSSFVVFGQGTKVEIK 2-21 539 DIQMTQSPSSLSASVGDRVTITCRASQSIHTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-22 540 DIQMTQSPSSLSASVGDRVTITCRASQSIHTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-23 541 DIQMTQSPSSLSASVGDRVTITCRASQTINTFLNWYQQKPGKAPKWYSASTLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTFTFGGGTKVEIK 2-24 542 DIQMTQSPSSLSASVGDRVTITCRASQTIRTYLNWYRQKPGKAPKLLIYDASTLQR GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYRTPPWTFGGGTKVEIK 2-25 543 DIQMTQSPSSLSASVGDRVTITCRSSQSISSYLNWYQQKPGEAPKLLIYGASRLRSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYSAPWTFGGGTKVEIK 2-26 544 DIQMTQSPSSLSASVGDRVTITCRASQSISGSLNWYQQKPGKAPKLLIYAESRLHS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSPPQTFGGGTKVEIK 2-27 545 DIQMTQSPSSLSASVGDRVTITCRASRSISTYLNWYQQKPGKAPKLLIYAASNLQG GVPSRLSGSGSGTDFTLTISSLQPEDFATYYCQQSHSIPRTFGGGTKVEIK 2-28 546 DIQMTQSPSSLSASVGDRVTITCRASQSIHTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK

TABLE 28 ACE2 Variable Heavy Chain CDRs SEQ SEQ SEQ ID ID ID Name NO CDRH1 NO CDRH2 NO CDRH3 3-10 547 FTFRSHAMS 576 SSISGGGASTYYA 605 CARVKYLTTSSGWPRPYFDNW 3-4 548 FTFSAYSMS 577 SAISGSGGSRYYA 606 CGRSKWPQANGAFDIW 3-7 549 FMFGNYAMS 578 AAISGSGGSTYYA 607 CAKDRGYSSSWYGGFDYW 3-1 550 FTFRNHAMA 579 SGISGSGGTTYYG 608 CARGTRFLQWSLPLDVW 3-5 551 FTIPNYAMS 580 SGISGAGASTYYA 609 CARHTWWKGAGFFDHW 3-6 552 FTFRNYAMA 581 SGISGSGGTTYYG 610 CARGTRFLEWSLPLDVW 3-15 553 FTIRNYAMS 582 SSISGGGASTYYA 611 CARVKYLTTSSGWPRPYFDNW 3-3 554 FTIPNYAMS 583 SGISGSGASTYYA 612 CARHTWWKGAGFFDHW 3-11 555 FTITNYAMS 584 SGISGSGAGTYYA 613 CARHAWWKGAGFFDHW 3-8 556 FTFRSHAMS 585 SSISGGGASTYYA 614 CARVKYLTTSSGWPRPYFDNW 3-2 557 FTITNYAMS 586 SGISGSGASTYYA 615 CARHTWWKGAGFFDHW 3-12 558 FTFRSHAMN 587 SAISGSGGSTNYA 616 CARGLKFLEWLPSAFDIW 3-14 559 FTFRSHAMS 588 SSISGGGASTYYA 617 CARVKYLTTSSGWPRPYFDNW 3-9 560 FTFRSYAMS 589 SSISGGGASTYYA 618 CARVKYLTTSSGWPRPYFDNW 3-13 561 FTITNYAMS 590 SGISGSGAGTYYA 619 CARHTWWKGAGFFDHW 3-16 562 FTFTNFAMS 591 SAISGRGGGTYYA 620 CARDAHGYYYDSSGYDDW 3-17 563 FTFRSYPMS 592 STISGSGGITYYA 621 CAKGVYGSTVTTCHW 3-18 564 FTLTSYAMS 593 SAISGSGVDTYYA 622 CARPTNWGFDYW 3-19 565 FTFINYAMS 594 STISTSGGNTYYA 623 CARADSNWASSAYW 3-2 566 FPFSTYAMS 595 SGISVSGGFTYYA 624 CARDPYSYGYYYYYGMDVW 3-21 567 FTFSTYAMG 596 SGISGGGVSTYYA 625 CARARNWGPSDYW 3-22 568 FIFSDYAMT 597 SAISGSAFYA 626 CARDATYSSSWYNWFDPW 3-23 569 FTFSDYAMT 598 SDISGSGGSTYYA 627 CARGTVTSFDFW 3-24 570 FTFSIYAMG 599 SFISGSGGSTYYA 628 CAKDYHSASWFSAAADYW 3-25 571 FTFASYAMT 600 SAISESGGSTYYA 629 CAREGQEYSSGSSYFDYW 3-26 572 FTFSEYAMS 601 SAITGSGGSTYYG 630 CARGSQTPYCGGDCPETFDYW 3-27 573 FTFDDYAMS 602 SGISGGGTSTYYA 631 CARDLYSSGWYGFDYW 3-28 574 FTFNNYAMN 603 SAISGSVGSTYYA 632 CARDNYDFWSGYYTNWFDPW 3-29 575 FTFTNHAMS 604 SAISGSGSNIYYA 633 CARDSLSVTMGRGVVTYYYYGMDFW

TABLE 29 ACE2 Variant Sequences Variable Light Chain SEQ SEQ SEQ ID ID ID Name NO CDRL1 NO CDRL2 NO CDRL3 3-10 634 RASQSIRKYLN 663 ASSTLQR 692 CQQSLSTPFTF 3-4 635 RASQNIKTYLN 664 AASKLQS 693 CQQSYSTSPTF 3-7 636 RASQTIYSYLN 665 ATSTLQG 694 CQHRGTF 3-1 637 RASRSIRRYLN 666 ASSSLQA 695 CQQSYSTLLTF 3-5 638 RASQSIGKYLN 667 ASSSLQS 696 CQQSYSPPFTF 3-6 639 RASRSISRYLN 668 AASSLQA 697 CQQSYSSLLTF 3-15 640 RASQSIGKYLN 669 ASSTLQR 698 CQQSLSPPFTF 3-3 641 RASQSIGRYLN 670 ASSSLQS 699 CQQSYSLPRTF 3-11 642 RASQSIGRYLN 671 AASSLKS 700 CQQSYSLPRTF 3-8 643 RASQSIGKYLN 672 ASSTLQR 701 CQQSLSTPFTF 3-2 644 RASQSIGRYLN 673 AASSLKS 702 CQQSYSLPLTF 3-12 645 RTSQSINTYLN 674 GASNVQS 703 CQQSYRIPRTF 3-14 646 RASQSIGKYLN 675 ASSTLQR 704 CQQSFSPPFTF 3-9 647 RASQSIGKYLN 676 ASSTLQR 705 CQQSFSTPFTF 3-13 648 RASQSIGRYLN 677 AASSLKS 706 CQQSYSLPRTF 3-16 649 RASQIIGSYLN 678 TTSNLQS 707 CQQSYITPWTF 3-17 650 RASQSISRYIN 679 EASSLES 708 CQQSHITPLTF 3-18 651 RASQSIYTYLN 680 SASNLHS 709 CQQSDTTPWTF 3-19 652 RASQSIATYLN 681 GASSLEG 710 CQQTFSSPFTF 3-2 653 RASQNINTYLN 682 SASSLQS 711 CQQSSLTPWTF 3-21 654 RASQGIATYLN 683 YASNLQS 712 CQQSYSTRFTF 3-22 655 RASERISNYLN 684 TASNLES 713 CQQSYTPPRTF 3-23 656 RASQSISSSLN 685 AASRLQD 714 CQQSYSTPRSF 3-24 657 RASQSISSHLN 686 RASTLQS 715 CQQTYNTPQTF 3-25 658 RASQSISSYLI 687 AASRLHS 716 CQQGYNTPRTF 3-26 659 RASPSISTYLN 688 TASRLQT 717 CQQTYSTPSSF 3-27 660 RASQNIAKYLN 689 GASGLQS 718 CQQSHSPPITF 3-28 661 RASQSIGTYLN 690 AASNLHS 719 CQESYSAPYTF 3-29 662 RASQSISPYLN 691 KASSLQS 720 CQQSSSTPYTF

TABLE 30 ACE2 Variant Sequences Variable Heavy Chain Name SEQ ID NO Amino Acid Sequence 3-10 721 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSHAMSWVRQAPGKGLEWVS SISGGGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR VKYLTTSSGWPRPYFDNWGQGTLVTVSS 3-4 722 EVQLLESGGGLVQPGGSLRLSCAASGFTFSAYSMSWVRQAPGKGLEWVS AISGSGGSRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGRS KWPQANGAFDIWGQGTLVTVSS 3-7 723 EVQLLESGGGLVQPGGSLRLSCAASGFMFGNYAMSWVRQAPGKGLEWV AAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA KDRGYSSSWYGGFDYWGQGTLVTVSS 3-1 724 EVQLLESGGGLVQPGGSLRLSCAASGFTFRNHAMAWVRQAPGKGLEWV SGISGSGGTTYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR GTRFLQWSLPLDVWGQGTLVTVSS 3-5 725 EVQLLESGGGLVQPGGSLRLSCAASGFTIPNYAMSWVRQAPGKGLEWVS GISGAGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR HTWWKGAGFFDHWGQGTLVTVSS 3-6 726 EVQLLESGGGLVQPGGSLRLSCAASGFTFRNYAMAWVRQAPGKGLEWV SGISGSGGTTYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR GTRFLEWSLPLDVWGQGTLVTVSS 3-15 727 EVQLLESGGGLVQPGGSLRLSCAASGFTIRNYAMSWVRQAPGKGLEWVS SISGGGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR VKYLTTSSGWPRPYFDNWGQGTLVTVSS 3-3 728 EVQLLESGGGLVQPGGSLRLSCAASGFTIPNYAMSWVRQAPGKGLEWVS GISGSGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR HTWWKGAGFFDHWGQGTLVTVSS 3-11 729 EVQLLESGGGLVQPGGSLRLSCAASGFTITNYAMSWVRQAPGKGLEWVS GISGSGAGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR HAWWKGAGFFDHWGQGTLVTVSS 3-8 730 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSHAMSWVRQAPGKGLEWVS SISGGGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR VKYLTTSSGWPRPYFDNWGQGTLVTVSS 3-2 731 EVQLLESGGGLVQPGGSLRLSCAASGFTITNYAMSWVRQAPGKGLEWVS GISGSGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR HTWWKGAGFFDHWGQGTLVTVSS 3-12 732 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSHAMNWVRQAPGKGLEWV SAISGSGGSTNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR GLKFLEWLPSAFDIWGQGTLVTVSS 3-14 733 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSHAMSWVRQAPGKGLEWVS SISGGGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR VKYLTTSSGWPRPYFDNWGQGTLVTVSS 3-9 734 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSYAMSWVRQAPGKGLEWVS SISGGGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR VKYLTTSSGWPRPYFDNWGQGTLVTVSS 3-13 735 EVQLLESGGGLVQPGGSLRLSCAASGFTITNYAMSWVRQAPGKGLEWVS GISGSGAGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR HTWWKGAGFFDHWGQGTLVTVSS 3-16 736 EVQLLESGGGLVQPGGSLRLSCAASGFTFTNFAMSWVRQAPGKGLEWVS AISGRGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DAHGYYYDSSGYDDWGQGTLVTVSS 3-17 737 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSYPMSWVRQAPGKGLEWVS TISGSGGITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKG VYGSTVTTCHWGQGTLVTVSS 3-18 738 EVQLLESGGGLVQPGGSLRLSCAASGFTLTSYAMSWVRQAPGKGLEWVS AISGSGVDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR PTNWGFDYWGQGTLVTVSS 3-19 739 EVQLLESGGGLVQPGGSLRLSCAASGFTFINYAMSWVRQAPGKGLEWVS TISTSGGNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARA DSNWASSAYWGQGTLVTVSS 3-2 740 EVQLLESGGGLVQPGGSLRLSCAASGFPFSTYAMSWVRQAPGKGLEWVS GISVSGGFTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DPYSYGYYYYYGMDVWGQGTLVTVSS 3-21 741 EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVS GISGGGVSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR ARNWGPSDYWGQGTLVTVSS 3-22 742 EVQLLESGGGLVQPGGSLRLSCAASGFIFSDYAMTWVRQAPGKGLEWVS AISGSAFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAT YSSSWYNWFDPWGQGTLVTVSS 3-23 743 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMTWVRQAPGKGLEWVS DISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR GTVTSFDFWGQGTLVTVSS 3-24 744 EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYAMGWVRQAPGKGLEWVS FISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKD YHSASWFSAAADYWGQGTLVTVSS 3-25 745 EVQLLESGGGLVQPGGSLRLSCAASGFTFASYAMTWVRQAPGKGLEWVS AISESGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARE GQEYSSGSSYFDYWGQGTLVTVSS 3-26 746 EVQLLESGGGLVQPGGSLRLSCAASGFTFSEYAMSWVRQAPGKGLEWVS AITGSGGSTYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR GSQTPYCGGDCPETFDYWGQGTLVTVSS 3-27 747 EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYAMSWVRQAPGKGLEWV SGISGGGTSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DLYSSGWYGFDYWGQGTLVTVSS 3-28 748 EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYAMNWVRQAPGKGLEWV SAISGSVGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR DNYDFWSGYYTNWFDPWGQGTLVTVSS 3-29 749 EVQLLESGGGLVQPGGSLRLSCAASGFTFTNHAMSWVRQAPGKGLEWVS AISGSGSNIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARD SLSVTMGRGVVTYYYYGMDFWGQGTLVTVSS

TABLE 31 ACE2 Variant Sequences Variable Light Chain SEQ ID Name NO Amino Acid Sequence 3-10 750 DIQMTQSPSSLSASVGDRVTITCRASQSIRKYLNWYQQKPGKAPKLLIYASST LQRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLSTPFTFGGGTKVEIK 3-4 751 DIQMTQSPSSLSASVGDRVTITCRASRSIRRYLNWYQQKPGKAPKLLIYASSSL QAGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTLLTFGQGTKVEIK 3-7 752 DIQMTQSPSSLSASVGDRVTITCRASQSIGRYLNWYQQKPGKAPKLLIYASSSL QSGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSLPRTFGQGTKVEIK 3-1 753 DIQMTQSPSSLSASVGDRVTITCRASQTIYSYLNWYQQKPGKAPKLLIYATST LQGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHRGTFGQGTKVEIK 3-5 754 DIQMTQSPSSLSASVGDRVTITCRASQSIGRYLNWYQQKPGKAPKLLIYAASS LKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSLPRTFGQGTKVEIK 3-6 755 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASSS LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSPPFTFGQGTKVEIK 3-15 756 DIQMTQSPSSLSASVGDRVTITCRASQNIKTYLNWYQQKPGKAPKLLIYAASK LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTSPTFGQGTKVEIK 3-3 757 DIQMTQSPSSLSASVGDRVTITCRASRSISRYLNWYQQKPGKAPKLLIYAASSL QAGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSSLLTFGQGTKVEIK 3-11 758 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASST LQRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLSPPFTFGQGTKVEIK 3-8 759 DIQMTQSPSSLSASVGDRVTITCRASQSIGRYLNWYQQKPGKAPKLLIYAASS LKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSLPLTFGQGTKVEIK 3-2 760 DIQMTQSPSSLSASVGDRVTITCRTSQSINTYLNWYQQKPGKAPKWYGASN VQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYRIPRTFGQGTKVEIK 3-12 761 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASST LQRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLSTPFTFGQGTKVEIK 3-14 762 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASST LQRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSFSTPFTFGQGTKVEIK 3-9 763 DIQMTQSPSSLSASVGDRVTITCRASQSIGRYLNWYQQKPGKAPKLLIYAASS LKSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSLPRTFGQGTKVEIK 3-13 764 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASST LQRGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSFSPPFTFGQGTKVEIK 3-16 765 DIQMTQSPSSLSASVGDRVTITCRASQIIGSYLNWYQQKPGKAPKLLIYTTSNL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYITPWTFGQGTKVEIK 3-17 766 DIQMTQSPSSLSASVGDRVTITCRASQSISRYINWYQQKPGKAPKLLIYEASSL ESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHITPLTFGQGTKVEIK 3-18 767 DIQMTQSPSSLSASVGDRVTITCRASQSIYTYLNWYQQKPGKAPKLLIYSASN LHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSDTTPWTFGQGTKVEIK 3-19 768 DIQMTQSPSSLSASVGDRVTITCRASQSIATYLNWYQQKPGKAPKLLIYGASS LEGGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTFSSPFTFGQGTKVEIK 3-2 769 DIQMTQSPSSLSASVGDRVTITCRASQNINTYLNWYQQKPGKAPKWYSASS LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSSLTPWTFGQGTKVEIK 3-21 770 DIQMTQSPSSLSASVGDRVTITCRASQGIATYLNWYQQKPGKAPKLLIYYASN LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTRFTFGQGTKVEIK 3-22 771 DIQMTQSPSSLSASVGDRVTITCRASERISNYLNWYQQKPGKAPKLLIYTASN LESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTPPRTFGQGTKVEIK 3-23 772 DIQMTQSPSSLSASVGDRVTITCRASQSISSSLNWYQQKPGKAPKLLIYAASRL QDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPRSFGQGTKVEIK 3-24 773 DIQMTQSPSSLSASVGDRVTITCRASQSISSHLNWYQQKPGKAPKLLIYRASTL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTYNTPQTFGQGTKVEIK 3-25 774 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLIWYQQKPGKAPKLLIYAASRL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYNTPRTFGQGTKVEIK 3-26 775 DIQMTQSPSSLSASVGDRVTITCRASPSISTYLNWYQQKPGKAPKLLIYTASRL QTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTYSTPSSFGQGTKVEIK 3-27 776 DIQMTQSPSSLSASVGDRVTITCRASQNIAKYLNWYQQKPGKAPKLLIYGASG LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSPPITFGQGTKVEIK 3-28 777 DIQMTQSPSSLSASVGDRVTITCRASQSIGTYLNWYQQKPGKAPKLLIYAASN LHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQESYSAPYTFGQGTKVEIK 3-29 778 DIQMTQSPSSLSASVGDRVTITCRASQSISPYLNWYQQKPGKAPKLLIYKASSL QSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSSSTPYTFGQGTKVEIK

TABLE 32 ACE2 Variable Heavy Chain CDRs SEQ SEQ SEQ ID ID ID Name NO CDRH1 NO CDRH2 NO CDRH3 4-51 779 PGTAIMG 920 ARISTSGGSTKYA 1062 CARTTVTTPPLIW 4-52 780 RSFSNSVMG 921 ARITWNGGSTYYA 1063 CATTENPNPRW 4-53 781 RTFGDDTMG 922 AAVSWSGSGVYYA 1064 CATDPPLFW 4-54 782 RTFSDARMG 923 GAVSWSGGTTVYA 1065 CATTEDPYPRW 4-49 783 RTFGDYIMG 924 AAINWSAGYTAYA 1066 CARASPNTGWHFDHW 4-55 784 SGLSINAMG 925 AAISWSGGSTYTAYA 1067 CAAYQAGWGDW 4-39 785 RTFSNAAMG 926 ARILWTGASRNYA 1068 CATTENPNPRW 4-56 786 FSLDYYGMG 927 AAISWNGDFTAYA 1069 CAKRANPTGAYFDYW 4-33 787 FTFSRHDMG 928 AGINWESGSTNYA 1070 CAADRGVYGGRWYRTSQYTW 4-57 788 LTFRNYAMG 929 AAIGSGGYTDYA 1071 CAVKPGWVARDPSQYNW 4-25 789 GTFSRYAMG 930 SAVDSGGSTYYA 1072 CAASPSLRSAWQW 4-58 790 FTLDYYDMG 931 AAVTWSGGSTYYA 1073 CAADRRGLASTRAADYDW 4-59 791 RTFGDYIMG 932 AAINWSAGYTPYA 1074 CATAPPLFCWHFDLW 4-6 792 RTFGDDIMG 933 AAIHWSAGYTRYA 1075 CATDPPLFWGHVDLW 4-61 793 RTFGDYIMG 934 AAINWSADYTPYA 1076 CATAPPNTGWHFDHW 4-3 794 RTFGDYIMG 935 AAINWSAGYTAYA 1077 CATATPNTGWHFDHW 4-62 795 RTFSDDTMG 936 AAINWSGGSTDYA 1078 CATDPPLFW 4-43 796 RTFGDDTMG 937 AGINWSGGNTYYA 1079 CATDPPLFW 4-5 797 RTFGDYIMG 938 AAINWTGGYTSYA 1080 CATDPPLFW 4-42 798 RTFGDDTMG 939 AAINWSGGNTYYA 1081 CATDPPLFW 4-63 799 RTFSDYTMG 940 AAINWSGGYTYYA 1082 CATDPPLFW 4-6 800 RTFGDYGMG 941 ATINWSGALTHYA 1083 CATLPFYDFW SGYYTGYYYMDVW 4-40 801 RTFSDDTMG 942 AGVTWSGSSTFYA 1084 CATDPPLFW 4-21 802 RTFSDDIMG 943 AAISWSGGNTHYA 1085 CATDPPLFW 4-64 803 RTFGDYIMG 944 AAINWSAGYTAYA 1086 CATASPNTGWHFDHW 4-47 804 FTFDDDYVMG 945 AAVSGSGDDTYYA 1087 CAADRRGLASTRAADYDW 4-65 805 RTFGDYIMG 946 AAINWSAGYTAYA 1088 CATEPPLSCWHFDLW 4-18 806 RTFGDYIMG 947 AAINWSGGYTPYA 1089 CATAPPNTGWHFDHW 4-66 807 RTFGDDTMG 948 AAINWSAGYTPYA 1090 CATDPPLFCCHFDLW 4-36 808 RTFSDDTMG 949 AAISWSGGTTRYA 1091 CATDPPLFW 4-67 809 RTFSDDTMG 950 AAINWSGDSTYYA 1092 CATDPPLFW 4-16 810 RTFSDDTMG 951 AAINWSGGTTRYA 1093 CATDPPLFW 4-11 811 RTFSDDAMG 952 AAIHWSGSSTRYA 1094 CATDPPLFW 4-68 812 RTFSDDTMG 953 GTINWSGGSTYYA 1095 CATDPPLFW 4-34 813 RTFGDYIMG 954 AAINWSGGYTPYA 1096 CATDPPLFW 4-28 814 RTFGDDTMG 955 AAINWNGGNTHYA 1097 CATDPPLFW 4-69 815 RTFSDDAMG 956 AAINWSGGTTRYA 1098 CATDPPLFW 4-7 816 RTFGDYIMG 957 AAINWSAGYTPYA 1099 CATDPPLFWGHVDLW 4-71 817 RTFSDDTMG 958 ASINWSGGSTYYA 1100 CATDPPLFW 4-23 818 RTFSDDAMG 959 AGISWNGGSIYYA 1101 CATDPPLFW 4-9 819 FTFDDYEMG 960 AAISWRGGTTYYA 1102 CAADRRGLAST RAGDYDW 4-72 820 RTFGDDTMG 961 AAINWSGGYTPYA 1103 CATDPPLFWGHVDLW 4-73 821 RTFSDDAMG 962 AAINWSGGSTRYA 1104 CATDPPLFW 4-29 822 VTLDDYAMG 963 AVINWSGGSTDYA 1105 CARGGGWVPSST SESLNWYFDRW 4-41 823 RTFGDYIMG 964 AAINWSGGTTPYA 1106 CATDPPLFCCHVDLW 4-74 824 LTFSDDTMG 965 AAVSWSGGNTYYA 1107 CATDPPLFW 4-75 825 RTFGDDTMG 966 AAINWTGGYTPYA 1108 CATDPPLFW 4-31 826 RTFGDYIMG 967 ATINWTAGYTYYA 1109 CATDPPLFCWHFDHW 4-32 827 RTFGDDTMG 968 AAINWSGGNTDYA 1110 CATDPPLFW 4-15 828 RTFGDYTMG 969 AAINWSGGNTYYA 1111 CATDPPLFW 4-14 829 RTFSDDTMG 970 AGINWSGNGVYYA 1112 CATDPPLFW 4-76 830 RTFGDYAMG 971 APINWSGGSTYYA 1113 CATDPPLFW 4-50 831 GTFSNSGMG 972 AVVNWSGRRTYYA 1114 CAVPWMDYNRRDW 4-17 832 QLANFASYAMG 973 AAITRSGSSTVYA 1115 CATTMNPNPRW 4-37 833 RTFSDDIMG 974 AAINWTGGSTYYA 1116 CATDPPLFW 4-44 834 RTFGDYIMG 975 AAINWSAGYTAYA 1117 CATARPNTGWHFDHW 4-77 835 RTFSDDTMG 976 GSINWSGGSTYYA 1118 CATDPPLFW 4-78 836 RTFSDDTMG 977 AGMTWSGSSTFYA 1119 CATDPPLFW 4-79 837 RTFGDYIMG 978 AAINWSGDYTDYA 1120 CATDPPLFW 4-8 838 RTFGDYIMG 979 GGINWSGGYTYYA 1121 CATDPPLFW 4-81 839 RTFSDDTMG 980 AAVNWSGGSTYYA 1122 CATDPPLFW 4-82 840 RTFGDYAMG 981 AAINWSGGYTRYA 1123 CATDPPLFW 4-83 841 RTFGDDTMG 982 AAINWSGGYTPYA 1124 CATDPPLFW 4-35 842 RTFGDYIMG 983 AAINWSAGYTAYA 1125 CARASPNTGWHFDRW 4-45 843 RTFGDYIMG 984 AAINWSGGYTHYA 1126 CATDPPLFW 4-84 844 RTFSDDTMG 985 AAITWSGGRTRYA 1127 CATDRPLFW 4-85 845 RTFGDYIMG 986 AAINWSGGYTAYA 1128 CATASPNTGWHFDHW 4-86 846 RTFSDDTMG 987 AAIHWSGSSTRYA 1129 CATDPPLFW 4-87 847 RTFSDYTMG 988 AAINWSGGTTYYA 1130 CATDPPLFW 4-88 848 RTFGDDTMG 989 AAINWSGDNTHYA 1131 CATDPPLFW 4-89 849 FAFGDNWIG 990 ASISSGGTTAYA 1132 CAHRGGWLRPWGYW 4-9 850 RTFSDDAMG 991 GRINWSGGNTYYA 1133 CATDPPLFW 4-91 851 RTFSDDTMG 992 GGISWSGGNTYYA 1134 CATDPPLFW 4-92 852 RTFSDDTMG 993 AAINWSGGSTYYA 1135 CATDPPLFW 4-46 853 RTFGDDTMG 994 AAINWSGGYTYYA 1136 CATDPPLFW 4-20 854 RTFGDYIMG 995 AAINWSADYTAYA 1137 CATDPPLFCWHFDHW 4-93 855 RTFSDDAMG 996 AAINWSGSSTYYA 1138 CATDPPLFW 4-4 856 RTFGDYIMG 997 AAINWIAGYTADA 1139 CAEPSPNTGWHFDHW 4-2 857 RTFGDDTMG 998 AAINWSGGNTPYA 1140 CATDPPLFW 4-94 858 RTFSDDTMG 999 AAINWSGDNTHYA 1141 CATDPPLFW 4-95 859 RTFGDYIMG 1000 AAINWSAGYTAYA 1142 CATAPPLFCWHFDHW 4-12 860 FTFGDYVMG 1001 AAINWNAGYTAYA 1143 CAKASPNTGWHFDHW 4-30 861 RTFGDYTMG 1002 AAINWTGGYTYYA 1144 CATDPPLFW 4-27 862 RTFGDYIMG 1003 AAINWSAGYTAYA 1145 CARATPNTGWHFDHW 4-22 863 RTFGDYIMG 1004 AAINWSGDNTHYA 1146 CATDPPLFW 4-96 864 RTFGDYIMG 1005 AAINWSAGYTPYA 1147 CATDPPLFCCHFDHW 4-97 865 RTFGDYIMG 1006 AAINWSAGYTAYA 1148 CATAPPNTGWHFDHW 4-98 866 FTWGDYTMG 1007 AAINWSGGNTYYA 1149 CAADRRGLASTRAADYDW 4-99 867 IPSTLRAMG 1008 AAVSSLGPFTRYA 1150 CAAKPGWVARDPSQYNW 4-100 868 FSFDDDYVMG 1009 AAINWSGGSTYYA 1151 CAADRRGLASTRAADYDW 4-101 869 RTFSNAAMG 1010 ARILWTGASRSYA 1152 CATTENPNPRW 4-102 870 GTFGVYHMG 1011 AAINMSGDDSAYA 1153 CAILVGPGQVEFDHW 4-103 871 FTFSSYYMG 1012 ARISGSTFYA 1154 CAALPFVCPSGSY SDYGDEYDW 4-104 872 RTFSGDFMG 1013 GRINWSGGNTYYA 1155 CPTDPPLFW 4-105 873 STLRDYAMG 1014 AAITWSGGSTAYA 1156 CASLLAGDRYFDYW 4-106 874 FTFDDYTMG 1015 AAITDNGGSKYYA 1157 CAADRRGLASTRAADYDW 4-107 875 GTFSSYGMG 1016 AAINWSGASTYYA 1158 CARDWRDRTWGNSLDYW 4-108 876 FSFDDDYVMG 1017 AAISWSEDNTYYA 1159 CAADRRGLASTRAADYDW 4-109 877 FSFDDDYVMG 1018 AAVSGSGDDTYYA 1160 CAADRRGLASTRAADYDW 4-110 878 NIAAINVMG 1019 AAISASGRRTDYA 1161 CARRVYYYDSSGPPG VTFDIW 4-111 879 IITSRYVMG 1020 AAISTGGSTIYA 1162 CARQDSSSPYFDYW 4-112 880 FSFDDDYVMG 1021 AAISNSGLSTYYA 1163 CAADRRGLASTRAADYDW 4-113 881 SISSINVMG 1022 ATMRWSTGSTYYA 1164 CAQRVRGFFGPLRTT PSWYEW 4-114 882 LTFILYRMG 1023 AAINNFGTTKYA 1165 CARTHYDFWSGYTS RTPNYFDYW 4-115 883 GTFSVYHMG 1024 AAISWSGGSTAYA 1166 CAAVNTWTSPSFDSW 4-116 884 RAFSTYGMG 1025 AGINWSGDTPYYA 1167 CAREVGPPPGYFDLW 4-117 885 RTFSDIAMG 1026 ASINWGGGNTYYA 1168 CAAKGIWDYLGRRDFGDW 4-118 886 RTFSSARMG 1027 AAISWSGDNTHYA 1169 CATTENPNPRW 4-119 887 FAFSSYAMG 1028 ATINGDDYTYYA 1170 CVATPGGYGLW 4-120 888 ITFRRHDMG 1029 AAIRWSSSSTVYA 1171 CAADRGVYGGRWYR TSQYTW 4-121 889 TAASFNPMG 1030 AAITSGGSTNYA 1172 CAAIAYEEGVYRWDW 4-122 890 NINIINYMG 1031 AAIHWNGDSTAYA 1173 CASGPPYSNYFAYW 4-123 891 FTFDDYAMG 1032 AAISGSGGSTAYA 1174 CAKIMGSGRPYFDHW 4-124 892 NIFTRNVMG 1033 AAITSSGSTNYA 1175 CARPSSDLQGGVDYW 4-125 893 RTFSSIAMG 1034 ASINWGGGNTIYA 1176 CAAKGIWDYLGRRDFGDW 4-126 894 IPSTLRAMG 1035 AAVSSLGPFTRYA 1177 CAAKPGWVARDPSEYNW 4-127 895 FTLDDSAMG 1036 AAITNGGSTYYA 1178 CARFARGSPYFDFW 4-128 896 SISSFNAMG 1037 AAIDWDGSTAYA 1179 CARGGGYYGSGSFEYW 4-129 897 NIFSDNIIG 1038 AYYTSGGSIDYA 1180 CARGTAVGRPPPGGMDVW 4-130 898 SISSIGAMG 1039 AAISSSGSSTVYA 1181 CARVPPGQAYFDSW 4-131 899 FTFDDYGMG 1040 ATITWSGDSTYYA 1182 CAKGGSWYYDSSGYYGRW 4-132 900 RTFSNYTMG 1041 SAISWSTGSTYYA 1183 CAADRYGPPWYDW 4-133 901 STNYMG 1042 AAISMSGDDTIYA 1184 CARIGLRGRYFDLW 4-134 902 GTFSSVGMG 1043 AVINWSGARTYYA 1185 CAVPWMDYNRRDW 4-135 903 RIFTNTAMG 1044 AAINWSGGSTAYA 1186 CARTSGSYSFDYW 4-136 904 EEFSDHWMG 1045 GAIHWSGGRTYYA 1187 CAADRRGLASTRAADYDW 4-137 905 RTFSSIAMG 1046 AAINWSGARTAYA 1188 CAAKGIWDYLGRRDFGDW 4-138 906 STSSLRTMG 1047 AAISSRDGSTIYA 1189 CARDDSSSPYFDYW 4-139 907 GGTFGSYAMG 1048 AAISIASGASGGT 1190 CATTMNPNPRW TNYA 4-140 908 RTFSNAAMG 1049 ARITWNGGSTFYA 1191 CATTENPNPRW 4-141 909 IILSDNAMG 1050 AAISWLGESTYYA 1192 CAADRRGLASTRAADYDW 4-142 910 RTFGDYIMG 1051 AAINWNGGYTAYA 1193 CATTSPNTGWHYYRW 4-143 911 FNFNWYPMG 1052 AAISWTGVSTYTAYA 1194 CARWGPGPAGGS PGLVGFDYW 4-144 912 SIRSVSVMG 1053 AAISWSGVGTAYA 1195 CAAYQRGWGDW 4-145 913 MTFRLYAMG 1054 GAINWLSESTYYA 1196 CAAKPGWVARDPSEYNW 4-146 914 RTFSDDAMG 1055 AAINWSGGSTYYA 1197 CATDPPLFW 4-147 915 GTFSVYAMG 1056 AAISMSGDDAAYA 1198 CAKISKDDGGKP RGAFFDSW 4-148 916 FALGYYAMG 1057 AAISSRDGSTAYA 1199 CARLATGPQAYFHHW 4-149 917 FNLDDYAMG 1058 AAISWDGGATAYA 1200 CARVGRGTTAFDSW 4-150 918 NTFSGGFMG 1059 ASIRSGARTYYA 1201 CAQRVRGFFGPL RTTPSWYEW 4-151 919 SIRSINIMG 1060 AAISWSGGSTVYA 1202 CASLLAGDRYFDYW

TABLE 33 ACE2 Variant Sequences Variable Heavy Chain SEQ Name ID Amino Acid Sequence 4-51 1203 EVQLVESGGGLVQPGGSLRLSCAASGPGTAIMGWFRQAPGKEREFVARISTSGGSTK YADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARTTVTTPPLIWGQGTLVTV SS 4-52 1204 EVQLVESGGGLVQPGGSLRLSCAASGRSFSNSVMGWFRQAPGKEREFVARITWNGGS TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQGTLVT VSS 4-53 1205 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAVSWSGS GVYYADSVKGRFTITADNSKNTAYLQMNSLKPENTAVYYCATDPPLFWGQGTLVTV SS 4-54 1206 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDARMGWFRQAPGKEREFVGAVSWSGG TTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTEDPYPRWGQGTLV TVSS 4-49 1207 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSAG YTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARASPNTGWHFDHWG QGTLVTVSS 4-55 1208 EVQLVESGGGLVQPGGSLRLSCAASGSGLSINAMGWFRQAPGKERESVAAISWSGGS TYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAYQAGWGDWGQGT LVTVSS 4-39 1209 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNAAMGWFRQAPGKEREFVARILWTGA SRNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQGTLV TVSS 4-56 1210 EVQLVESGGGLVQPGGSLRLSCAASGFSLDYYGMGWFRQAPGKERESVAAISWNGD FTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKRANPTGAYFDYWGQ GTLVTVSS 4-33 1211 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRHDMGWFRQAPGKEREFVAGINWESGS TNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRGVYGGRWYRTSQ YTWGQGTLVTVSS 4-57 1212 EVQLVESGGGLVQPGGSLRLSCAASGLTFRNYAMGWFRQAPGKEREFVAAIGSGGY TDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVKPGWVARDPSQYNW GQGTLVTVSS 4-25 1213 EVQLVESGGGLVQPGGSLRLSCAASGGTFSRYAMGWFRQAPGKEREWVSAVDSGGS TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAASPSLRSAWQWGQGTL VTVSS 4-58 1214 EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYDMGWFRQAPGKEREFVAAVTWSGG STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADYD WGQGTLVTVSS 4-59 1215 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSAG YTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPLFCWHFDLWGQ GTLVTVSS 4-6 1216 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDIMGWFRQAPGKEREFVAAIHWSAG YTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGHVDLWGQ GTLVTVSS 4-61 1217 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSADY TPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPNTGWHFDHWGQG TLVTVSS 4-3 1218 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSAGY TAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATATPNTGWHFDHWGQ GTLVTVSS 4-62 1219 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWSGG STDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-43 1220 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAGINWSGG NTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-5 1221 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWTGG YTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-42 1222 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKERECVAAINWSGG NTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-63 1223 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDYTIMGWFRQAPGKEREFVAAINWSGG YTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-6 1224 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYGMGWFRQAPGKEREFVATINWSGA LTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATLPFYDFWSGYYTGY yymdvwgqgtlvtvss 4-40 1225 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFLAGVTWSGS STFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-21 1226 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDIMGWFRQAPGKEREFVAAISWSGGN THYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVSS 4-64 1227 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSAG YTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATASPNTGWHFDHWG QGTLVTVSS 4-47 1228 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDDYVMGWFRQAPGKEREFVAAVSGSG DDTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADY DWGQGTLVTVSS 4-65 1229 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSAG YTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATEPPLSCWHFDLWGQ GTLVTVSS 4-18 1230 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSGGY TPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPNTGWHFDHWGQG TLVTVSS 4-66 1231 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREIVAAINWSAG YTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCCHFDLWGQ GTLVTVSS 4-36 1232 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAISWSGGT TRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVSS 4-67 1233 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWSGD STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-16 1234 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWSGG TTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-11 1235 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAIHWSGSS TRYADSVRGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVSS 4-68 1236 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKERELVGTINWSGGS TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVSS 4-34 1237 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSGG YTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-28 1238 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKERELVAAINWNGG NTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-69 1239 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAINWSGG TTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-7 1240 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSAG YTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGHVDLWGQ GTLVTVSS 4-71 1241 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREWVASINWSGG STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-23 1242 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAGISWNGG SIYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-9 1243 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYEMGWFRQAPGKEREFVAAISWRGG TTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAGDYD WGQGTLVTVSS 4-72 1244 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWSGG YTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGHVDLWGQ GTLVTVSS 4-73 1245 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAINWSGG STRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-29 1246 EVQLVESGGGLVQPGGSLRLSCAASGVTLDDYAMGWFRQAPGKEREFVAVINWSGG STDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGGGWVPSSTSESLN WYFDRWGQGTLVTVSS 4-41 1247 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSGGT TPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCCHVDLWGQG TLVTVSS 4-74 1248 EVQLVESGGGLVQPGGSLRLSCAASGLTFSDDTMGWFRQAPGKEREFVAAVSWSGG NTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-75 1249 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWTGG YTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-31 1250 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVATINWTAG YTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCWHFDHWGQ GTLVTVSS 4-32 1251 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWSGG NTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-15 1252 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYTMGWFRQAPGKEREFVAAINWSGG NTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-14 1253 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAGINWSGN GVYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-76 1254 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYAMGWFRQAPGKERELVAPINWSGG STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-50 1255 EVQLVESGGGLVQPGGSLRLSCAASGGTFSNSGMGWFRQAPGKERELVAVVNWSGR RTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVPWMDYNRRDWGQG TLVTVSS 4-17 1256 EVQLVESGGGLVQPGGSLRLSCAASGQLANFASYAMGWFRQAPGKEREFVAAITRSG SSTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTMNPNPRWGQGTL VTVSS 4-37 1257 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDIMGWFRQAPGKEREFVAAINWTGGS TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVSS 4-44 1258 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSAGY TAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATARPNTGWHFDHWGQ GTLVTVSS 4-77 1259 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREWVGSINWSGG STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-78 1260 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAGMTWSGS STFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-79 1261 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERECVAAINWSGD YTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-8 1262 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVGGINWSGG YTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-81 1263 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAVNWSGG STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-82 1264 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYAMGWFRQAPGKEREFVAAINWSGG YTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-83 1265 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWSGG YTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-35 1266 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSAG YTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARASPNTGWHFDRWG QGTLVTVSS 4-45 1267 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSGG YTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-84 1268 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAITWSGG RTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDRPLFWGQGTLVTV SS 4-85 1269 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSGG YTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATASPNTGWHFDHWG QGTLVTVSS 4-86 1270 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAIHWSGSS TRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVSS 4-87 1271 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDYTMGWFRQAPGKEREWVAAINWSGG TTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-88 1272 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWSGD NTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-89 1273 EVQLVESGGGLVQPGGSLRLSCAASGFAFGDNWIGWFRQAPGKEREWVASISSGGTT AYADNVKGRFTIIADNSKNTAYLQMNSLKPEDTAVYYCAHRGGWLRPWGYWGQGT LVTVSS 4-9 1274 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVGRINWSGG NTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-91 1275 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVGGISWSGG NTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-92 1276 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWSGG STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-46 1277 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWSGG YTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-20 1278 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSAD YTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCWHFDHWGQ GTLVTVSS 4-93 1279 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAINWSGSS TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVSS 4-4 1280 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREMVAAINWIAG YTADADSVRRLFTITADNNKNTAHLMMNLLKPENTAVYYCAEPSPNTGWHFDHWG QGTLVTVSS 4-2 1281 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWSGG NTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTVS S 4-94 1282 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWSGD NTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-95 1283 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSAGY TAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPLFCWHFDHWGQG TLVTVSS 4-12 1284 EVQLVESGGGLVQPGGSLRLSCAASGFTFGDYVMGWFRQAPGKEREIVAAINWNAG YTAYADSVRGLFTITADNSKNTAYLQMNSLKPEDTAVYYCAKASPNTGWHFDHWG QGTLVTVSS 4-30 1285 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYTMGWFRQAPGKEREFVAAINWTGG YTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-27 1286 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSAGY TAYADSVKGLFTITADNSKNTAYLQMNILKPEDTAVYYCARATPNTGWHFDHWGQG TLVTVSS 4-22 1287 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSGD NTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTLVTV SS 4-96 1288 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSAGY TPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCCHFDHWGQG TLVTVSS 4-97 1289 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSAG YTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPNTGWHFDHWG QGTLVTVSS 4-98 1290 EVQLVESGGGLVQPGGSLRLSCAASGFTWGDYTMGWFRQAPGKEREFVAAINWSGG NTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADYD WGQGTLVTVSS 4-99 1291 EVQLVESGGGLVQPGGSLRLSCAASGIPSTLRAMGWFRQAPGKEREFVAAVSSLGPF TRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKPGWVARDPSQYNWG QGTLVTVSS 4-100 1292 EVQLVESGGGLVQPGGSLRLSCAASGFSFDDDYVMGWFRQAPGKEREFVAAINWSG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADY DWGQGTLVTVSS 4-101 1293 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNAAMGWFRQAPGKEREFVARILWTGA SRSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQGTLVT VSS 4-102 1294 EVQLVESGGGLVQPGGSLRLSCAASGGTFGVYHMGWFRQAPGKEREGVAAINMSGD DSAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAILVGPGQVEFDHWGQ GTLVTVSS 4-103 1295 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMGWFRQAPGKEREFVARI-- SGSTFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAALPFVCPSGSYSDY GDEYDWGQGTLVTVSS 4-104 1296 EVQLVESGGGLVQPGGSLRLSCAASGRTFSGDFMGWFRQAPGKEREFVGRINWSGG NTYYADSVRGLFTITADNNKNTAYLMMNLLKPEDTAVYYCPTDPPLFWGLGTLVTW SS 4-105 1297 EVQLVESGGGLVQPGGSLRLSCAASGSTLRDYAMGWFRQAPGKERESVAAITWSGG STAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASLLAGDRYFDYWGQG TLVTVSS 4-106 1298 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYTMGWFRQAPGKEREFVAAITDNGGS KYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADYD WGQGTLVTVSS 4-107 1299 EVQLVESGGGLVQPGGSLRLSCAASGGTFSSYGMGWFRQAPGKEREFVAAINWSGA STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDWRDRTWGNSLDY WGQGTLVTVSS 4-108 1300 EVQLVESGGGLVQPGGSLRLSCAASGFSFDDDYVMGWFRQAPGKEREFVAAISWSE DNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADY DWGQGTLVTVSS 4-109 1301 EVQLVESGGGLVQPGGSLRLSCAASGFSFDDDYVMGWFRQAPGKEREFVAAVSGSG DDTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADY DWGQGTLVTVSS 4-110 1302 EVQLVESGGGLVQPGGSLRLSCAASGNIAAINVMGWFRQAPGKEREFVAAISASGRR TDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARRVYYYDSSGPPGVTF DIWGQGTLVTVSS 4-111 1303 EVQLVESGGGLVQPGGSLRLSCAASGIITSRYVMGWFRQAPGKEREGVAAISTGGSTI YADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARQDSSSPYFDYWGQGTLV TVSS 4-112 1304 EVQLVESGGGLVQPGGSLRLSCAASGFSFDDDYVMGWFRQAPGKEREFVAAISNSGL STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADYD WGQGTLVTVSS 4-113 1305 EVQLVESGGGLVQPGGSLRLSCAASGSISSINVMGWFRQAPGKEREFVATMRWSTGS TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAQRVRGFFGPLRTTPSWY EWGQGTLVTVSS 4-114 1306 EVQLVESGGGLVQPGGSLRLSCAASGLTFILYRMGWFRQAPGKEREFVAAINNFGTT KYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARTHYDFWSGYTSRTPNY FDYWGQGTLVTVSS 4-115 1307 EVQLVESGGGLVQPGGSLRLSCAASGGTFSVYHMGWFRQAPGKEREPVAAISWSGG STAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAVNTWTSPSFDSWGQ GTLVTVSS 4-116 1308 EVQLVESGGGLVQPGGSLRLSCAASGRAFSTYGMGWFRQAPGKEREFVAGINWSGD TPYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAREVGPPPGYFDLWGQ GTLVTVSS 4-117 1309 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDIAMGWFRQAPGKEREFVASINWGGGN TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKGIWDYLGRRDFGD WGQGTLVTVSS 4-118 1310 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSARMGWFRQAPGKEREFVAAISWSGDN THYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQGTLVT VSS 4-119 1311 EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYAMGWFRQAPGKEREWVATINGDDY TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCVATPGGYGLWGQGTLVT VSS 4-120 1312 EVQLVESGGGLVQPGGSLRLSCAASGITFRRHDMGWFRQAPGKEREFVAAIRWSSSS TVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRGVYGGRWYRTSQ YTWGQGTL VTVSS 4-121 1313 EVQLVESGGGLVQPGGSLRLSCAASGTAASFNPMGWFRQAPGKEREFVAAITSGGST NYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAIAYEEGVYRWDWGQG TLVTVSS 4-122 1314 EVQLVESGGGLVQPGGSLRLSCAASGNINIINYMGWFRQAPGKEREGVAAIHWNGDS TAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASGPPYSNYFAYWGQGT LVTVSS 4-123 1315 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYAMGWFRQAPGKERESVAAISGSGGS TAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKIMGSGRPYFDHWGQG TLVTVSS 4-124 1316 EVQLVESGGGLVQPGGSLRLSCAASGNIFTRNVMGWFRQAPGKEREFVAAITSSGST NYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARPSSDLQGGVDYWGQGT LVTVSS 4-125 1317 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSIAMGWFRQAPGKEREFVASINWGGGN TIYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKGIWDYLGRRDFGDW GQGTLVTVSS 4-126 1318 EVQLVESGGGLVQPGGSLRLSCAASGIPSTLRAMGWFRQAPGKEREFVAAVSSLGPFT RYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKPGWVARDPSEYNWG QGTLVTVSS 4-127 1319 EVQLVESGGGLVQPGGSLRLSCAASGFTLDDSAMGWFRQAPGKEREWVAAITNGGS TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARFARGSPYFDFWGQGT LVTVSS 4-128 1320 EVQLVESGGGLVQPGGSLRLSCAASGSISSFNAMGWFRQAPGKERESVAAIDWDGST AYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGGGYYGSGSFEYWGQ GTLVTVSS 4-129 1321 EVQLVESGGGLVQPGGSLRLSCAASGNIFSDNIIGWFRQAPGKEREMVAYYTSGGSID YADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGTAVGRPPPGGMDVWG QGTLVTVSS 4-130 1322 EVQLVESGGGLVQPGGSLRLSCAASGSISSIGAMGWFRQAPGKEREGVAAISSSGSST VYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVPPGQAYFDSWGQGTL VTVSS 4-131 1323 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYGMGWFRQAPGKERELVATITWSGD STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKGGSWYYDSSGYYGR WGQGTLVTVSS 4-132 1324 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYTMGWFRQAPGKEREWVSAISWSTGS TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRYGPPWYDWGQGT LVTVSS 4-133 1325 EVQLVESGGGLVQPGGSLRLSCAASGSTNYMGWFRQAPGKEREGVAAISMSGDDTIY ADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARIGLRGRYFDLWGQGTLVT VSS 4-134 1326 EVQLVESGGGLVQPGGSLRLSCAASGGTFSSVGMGWFRQAPGKERELVAVINWSGA RTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVPWMDYNRRDWGQG TLVTVSS 4-135 1327 EVQLVESGGGLVQPGGSLRLSCAASGRIFTNTAMGWFRQAPGKEREGVAAINWSGGS TAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARTSGSYSFDYWGQGTL VTVSS 4-136 1328 EVQLVESGGGLVQPGGSLRLSCAASGEEFSDHWMGWFRQAPGKEREFVGAIHWSGG RTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADYD WGQGTLVTVSS 4-137 1329 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSIAMGWFRQAPGKEREFVAAINWSGAR TAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKGIWDYLGRRDFGD WGQGTLVTVSS 4-138 1330 EVQLVESGGGLVQPGGSLRLSCAASGSTSSLRTMGWFRQAPGKEREGVAAISSRDGS TIYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDDSSSPYFDYWGQGTL VTVSS 4-139 1331 EVQLVESGGGLVQPGGSLRLSCAASGGGTFGSYAMGWFRQAPGKEREFVAAISIASG ASGGTTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTMNPNPRWGQ GTLVTVSS 4-140 1332 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNAAMGWFRQAPGKEREFVARITWNGG STFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQGTLVT VSS 4-141 1333 EVQLVESGGGLVQPGGSLRLSCAASGIILSDNAMGWFRQAPGKEREFVAAISWLGES TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAADYDW GQGTLVTVSS 4-142 1334 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWNGG YTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTSPNTGWHYYRWG QGTLVTVSS 4-143 1335 EVQLVESGGGLVQPGGSLRLSCAASGFNFNWYPMGWFRQAPGKERESVAAISWTGV STYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARWGPGPAGGSPGL VGFDYWGQGTLVTVSS 4-144 1336 EVQLVESGGGLVQPGGSLRLSCAASGSIRSVSVMGWFRQAPGKEREAVAAISWSGVG TAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAYQRGWGDWGQGTLV TVSS 4-145 1337 EVQLVESGGGLVQPGGSLRLSCAASGMTFRLYAMGWFRQAPGKEREFVGAINWLSE STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKPGWVARDPSEYNW GQGTLVTVSS 4-146 1338 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAINWSGG STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTMVTV SS 4-147 1339 EVQLVESGGGLVQPGGSLRLSCAASGGTFSVYAMGWFRQAPGKEREGVAAISMSGD DAAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKISKDDGGKPRGAFF DSWGQGTLVTVSS 4-148 1340 EVQLVESGGGLVQPGGSLRLSCAASGFALGYYAMGWFRQAPGKERESVAAISSRDGS TAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARLATGPQAYFHHWGQG TLVTVSS 4-149 1341 EVQLVESGGGLVQPGGSLRLSCAASGFNLDDYAMGWFRQAPGKERESVAAISWDGG ATAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVGRGTTAFDSWGQG TLVTVSS 4-150 1342 EVQLVESGGGLVQPGGSLRLSCAASGNTFSGGFMGWFRQAPGKEREFVASIRSGART YYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAQRVRGFFGPLRTTPSWYE WGQGTLVTVSS 4-151 1343 EVQLVESGGGLVQPGGSLRLSCAASGSIRSINIMGWFRQAPGKEREAVAAISWSGGST VYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASLLAGDRYFDYWGQGTL VTVSS

TABLE 34 SARS-CoV-2 S1 Variable Heavy Chain CDRs SEQ SEQ SEQ ID ID ID Name NO CDRH1 NO CDRH2 NO CDRH3  5-1 1344 GTFSSIGMG 1524 AAISWDGGATAYA 1704 CAKEDVGKPFDW 5-2 1345 LRFDDYAMG 1525 AIKFSGGTTDYA 1705 CASWDGLIGLDAYEYDW 5-3 1346 SIFSIDVMG 1526 AGISWSGDSTLYA 1706 CAAFDGYTGSDW 5-4 1347 FTLADYAMG 1527 AVITCSGGSTDYA 1707 CAADDCYIGCGW 5-5 1348 RTFSSIAMG 1528 AEITEGGISPSGD 1708 CAAELHSSDYTSPG NIYYA AESDYGW 5-6 1349 PTFSSYAMMG 1529 AAINNFGTTKYA 1709 CAASASDYGLGLEL FHDEYNW 5-7 1350 STGYMG 1530 AAIHSGGSTNYA 1710 CATVATALIW 5-8 1351 RPFSEYTMG 1531 SSIHWGGRGTNYA 1711 CAAELHSSDYTSPGAYAW 5-9 1352 LTLSTYGMG 1532 AHIPRSTYSPYYA 1712 CAAIGDGAVW 5-10 1353 FTFNNHNMG 1533 AAISSYSHTAYA 1713 CALQPFGASNYRW 5-11 1354 GIYRVMG 1534 ASISSGGGINYA 1714 CAAESWGRQW 5-12 1355 YTDSNLWMG 1535 AINRSTGSTSYA 1715 CATSGSGSPNW 5-13 1356 FTFDYYTMG 1536 AAIRSSGGLFYA 1716 CAAYLDGYSGSW 5-14 1357 GIFSINVMG 1537 SAIRWNGGNTAYA 1717 CAGFDGYTGSDW 5-15 1358 FTFDGAAMG 1538 ATIRWTNSTDYA 1718 CARGRYGIVERW 5-16 1359 RTHSIYPMG 1539 AAIHSGGATVYA 1719 CAARRWIPPGPIW 5-17 1360 PTFSIYAMG 1540 AGIRWSDVYTQYA 1720 CALDIDYRDW 5-18 1361 LTFDDNIHVM 1541 AAIHWSGGSTIYA 1721 CAADVYPQDYGLGYVEGK G MYYGMDW 5-19 1362 LTLDYYAMG 1542 ASINWSGGSTYYA 1722 CAAYGSGEFDW 5-20 1363 RTIVPYTMG 1543 AAISPSAFTEYA 1723 CAARRWGYDW 5-21 1364 GTFTTYHMG 1544 AHISTGGATNYA 1724 CATFPAIVTDSDYDLGNDW 5-22 1365 FTFNVFAMG 1545 AAINWSDSRTDYA 1725 CASGSDNRARELSRYEYVW 5-23 1366 SIFSIDVMG 1546 AAISWSGESTLYA 1726 CAAFDGYSGSDW 5-24 1367 FTFSSYSMG 1547 AAISSYSHTAYA 1727 CALQPFGASSYRW 5-25 1368 NTFSINVMG 1548 AAIHWSGDSTLYA 1728 CAAFDGYSGNHW 5-26 1369 RTISSYIMG 1549 ARIYTGGDTIYA 1729 CAARTSYNGRYDYIDDYSW 5-27 1370 RANSINWMG 1550 ATITPGGNTNYA 1730 CAAAAGSTWYGTLYEYDW 5-28 1371 GTFSVFAMG 1551 AEITAGGSTYYA 1731 CAVDGPFGW 5-29 1372 FTFDDYPMG 1552 ASVLRGGYTWYA 1732 CAKDWATGLAW 5-30 1373 FALGYYAMG 1553 AGIRWTDAYTEYA 1733 CAADVSPSYGSRWYW 5-31 1374 RTLDIHVMG 1554 AVINWTGESTLYA 1734 CAAFDGYTGNYW 5-32 1375 FTPDNYAMG 1555 AALGWSGVTTYHY 1735 CASDESDAANW YA 5-33 1376 FTFDDYAMG 1556 ATIMWSGNTTYYA 1736 CATNDDDV 5-34 1377 RTFSRYIMG 1557 AAISWSGGDNTYYA 1737 CAAYRIVVGGTSPGDWRW 5-35 1378 PTFSIYAMG 1558 AGISWNGGSTNYA 1738 CALRRRFGGQEW 5-36 1379 RTFSLNAMG 1559 AAISCGGGSTYA 1739 CAADNDMGYCSW 5-37 1380 STFSINAMG 1560 GGISRSGATTNYA 1740 CAADGVPEYSDYASGPVW 5-38 1381 RTFSMHAMG 1561 ASISSQGRTNYA 1741 CAAEVRNGSDYLPIDW 5-39 1382 VTLDLYAMG 1562 AGIRWTDAYTEYA 1742 CAVDIDYRDW 5-40 1383 LPFTINVMG 1563 AAIHWSGLTTFYA 1743 CAELDGYFFAHW 5-41 1384 RAFSNYAMG 1564 AWINNRGTTDYADS 1744 CASTDDYGVDW GSTYYA 5-42 1385 FTPDDYAMG 1565 ASIGYSGRSNSYNY 1745 CAIAHGSSTYNW YA 5-43 1386 FTLNYYGMG 1566 AAITSGGAPHYA 1746 CASAYDRGIGYDW 5-44 1387 LPFSTKSMG 1567 AAIHWSGLTSYA 1747 CAADRAADFFAQRDEYDW 5-45 1388 RTFSINAMG 1568 AAISWSGESTQYA 1748 CAAFDGGSGTQW 5-46 1389 EEFSDHWMG 1569 AAIHWSGDSTHRNY 1749 CATVGITLNW A 5-47 1390 FTFGSYDMG 1570 TAINWSGARTAYA 1750 CAARSVYSYEYNW 5-48 1391 LPLDLYAMG 1571 AGIRWSDAYTEYA 1751 CALDIDYRHW 5-49 1392 RTSTVNGMG 1572 ASISQSGAATAYA 1752 CAADRTYSYSSTGYYW 5-50 1393 FSLDYYGMG 1573 AAITSGGTPHYA 1753 CASAYNPGIGYDW 5-51 1394 RPNSINWMG 1574 ATITPGGNTNYA 1754 CAAAAGTTWYGTLYEYDW 5-52 1395 EKFSDHWMG 1575 ATITFSGARTAYA 1755 CAALIKPSSTDRIFEEW 5-53 1396 LTVVPYAMG 1576 AAIRRSAVTNYA 1756 CAARRWGYHYW 5-54 1397 TTFNFNVMG 1577 AVISWTGESTLYA 1757 CAAFDGYTGRDW 5-55 1398 IDVNRNAMG 1578 AAITWSGGWRYYA 1758 CATTFGDAGIPDQYDFGW 5-56 1399 RTFSSNMG 1579 ARIFGGDRTLYA 1759 CADINGDW 5-57 1400 GTFSMGWIR 1580 GCIGWITYYA 1760 CAPFGW 5-58 1401 CTLDYYAMG 1581 AGIRWTDAYTEYA 1761 CAADVSPSYGGRWYW 5-59 1402 LTFSLYRMC 1582 SCISNIDGSTYYA 1762 CAADLLGDSDYEPSSGFGW 5-60 1403 RSFSSHRMG 1583 AAIMWSGSHRNYA 1763 CAAIAYEEGVYRWDW 5-61 1404 RIIVPNTMG 1584 TGISPSAFTEYA 1764 CAAHGWGCHW 5-62 1405 SIFIISMG 1585 TGINWSGGSTTYA 1765 CAASAIGSGALRRFEYDW 5-63 1406 FSLDYYDMG 1586 AALGWSGGSTDYA 1766 CAAGNGGRYGIVERW 5-64 1407 TSISNRVMG 1587 ARIYTGGDTLYA 1767 CAARKIYRSLSYYGDYDW 5-65 1408 NIDRLYAMG 1588 AAIDSDGSTDYA 1768 CAALIDYGLGFPIEW 5-66 1409 NTFTINVMG 1589 AAINWNGGTTLYA 1769 CAAFDGYSGIDW 5-67 1410 FNVNDYAMG 1590 AGITSSVGVTNYA 1770 CAADIFFVNW 5-68 1411 FTFDHYTMG 1591 AAISGSENVTSYA 1771 CAAEPYIPVRTMRHM TFLTW 6-1 1412 RTFGNYNMG 1592 ATINSLGGTSYA 1772 CARVDYYMDVW 6-2 1413 FTMSSSWMG 1593 TVISGVGTSYA 1773 CARGPDSSGYGFDYW 6-3 1414 FTFSPSWMG 1594 ATINEYGGRNYA 1774 CARVDRDFDYW 6-4 1415 FTRDYYTMG 1595 AAISRSGSLTSYA 1775 CANLAYYDSSGYYDYW 6-5 1416 RTFTMG 1596 ASTNSAGSTNYA 1776 CTTVDQYFDYW 6-6 1417 TTLDYYAMG 1597 AAISWSGGSTAYA 1777 CAREDYYDSSGYSW 6-7 1418 FTFSSYWMG 1598 ATINWSGVTAYA 1778 CARADDYFDYW 6-8 1419 FTLSGIWMG 1599 AIITTGGRTTYA 1779 CAGYSTFGSSSAYYYYSMD VG 6-9 1420 FTFDYYAMG 1600 SAIDSEGRTSYA 1780 CARWGPFDIW 6-10 1421 SIASIHAMG 1601 AAISRSGGFGSYA 1781 CARDDKYYDSSGYPAYFQH W 6-11 1422 LAFNAYAMG 1602 ATIGWSGANTYYA 1782 CASDPPGW 6-12 1423 STYTTYSMG 1603 AAISGSENVTSYA 1783 CARVDDYMDVW 6-13 1424 LTFNDYAMG 1604 AHIPRSTYSPYYA 1784 CAFLVGPQGVDHGAFDVW 6-14 1425 ITFRFKAMG 1605 AAVSWDGRNTYYA 1785 CASDYYYMDVW 6-15 1426 STVLINAMG 1606 AAVRWSDDYTYYA 1786 CAKEGRAGSLDYW 6-16 1427 FTFDDAAMG 1607 AHISWSGGSTYYA 1787 CATFGATVTATNDAFDIW 6-17 1428 NTGSTGYMG 1608 AGVINDGSTVYA 1788 CARLATSHQDGTGYLFDYW 6-18 1429 LTFRNYAMG 1609 AGMMWSGGTTTYA 1789 CAREGYYYDSSGYLNYFDY W 6-19 1430 SILSIAVMG 1610 AAISPSAVTTYYA 1790 CAIGYYDSSGYFDYW 6-20 1431 STLPYHAMG 1611 AAITWNGASTSYA 1791 CARDRYYDTSASYFESETW 6-21 1432 TLFKINAMG 1612 AAITSSGSNIDYTYY 1792 CARSNTGWYSFDYW A 6-22 1433 RTFSEVVMG 1613 ATIHSSGSTSYA 1793 CVRVTSDYSMDSW 6-23 1434 SIFSMNTMG 1614 ALINRSGGGINYA 1794 CVRLSSGYYDFDYW 6-24 1435 FTLDYYAMG 1615 AAINWSGDNTHYA 1795 CARAPFYCTTTKCQDNYYY MDVW 6-25 1436 LTFGTYTMG 1616 AAISRFGSTYYA 1796 CARGGDYDFWSVDYMDVW 6-26 1437 DTFSTSWMG 1617 ATINTGGGTNYA 1797 CARVTTSFDYW 6-27 1438 ITFRFKAMG 1618 ASISRSGTTYYA 1798 CATDYSAFDMW 6-28 1439 DTYGSYWMG 1619 ATITSDDRTNYA 1799 CARVTSSLSGMDVW 6-29 1440 YTLKNYYAM 1620 AAIIWTGESTLDA 1800 CAREGYYDSSGYYW G 6-30 1441 FAFGDSWMG 1621 ATINWSGVTAYA 1801 CARADGYFDYW 6-31 1442 DTFSANRMG 1622 ASITWSSANTYYA 1802 CATFNWNDEGFDFW 6-32 1443 FTLDYYDMG 1623 ALISWSGGSTYYA 1803 CATDFYGWGTRERDAFDIW 6-33 1444 TFQRINHMG 1624 ATINTGGQPNYA 1804 CASLIAAQDYYFDYW 6-34 1445 SAFRSNAMG 1625 AHISWSSKSTYYA 1805 CATYCSSTSCFDYW 6-35 1446 FTLAYYAMG 1626 AAISMSGDDTIYA 1806 CARELGYSSTVWPW 6-36 1447 FDFSVSWMG 1627 TAITWSGDSTNYA 1807 CASLLHTGPSGGNYFDYW 6-37 1448 HTFSTSWMG 1628 ATINSLGGTNYA 1808 CARVSSGDYGMDVW 6-38 1449 NTFSGGFMG 1629 AVISSLSSKSYA 1809 CAKVDSGYDYW 6-39 1450 FTFSPSWMG 1630 AAISWSGGSTAYA 1810 CHGLGEGDPYGDYEGYFDL W 6-40 1451 FTFSDYWMG 1631 ARVWWNGGSAYYA 1811 CAREVLRQQVVLDYW 6-41 1452 FTFSTSWMG 1632 ASINEYGGRNYA 1812 CAGLHYYYDSSGYNPTEYY GMDVW 6-42 1453 DTYGSYWMG 1633 AVITSGGSTNYA 1813 CTHVQNSYYYAMDVW 6-43 1454 RTFSSYAMM 1634 ASVNWDASQINYA 1814 CTTLGAVYFDSSGYHDYFD G YW 6-44 1455 GTFGVYHMG 1635 GRITWTDGSTYYA 1815 CFGLLEVYDMTFDYW 6-45 1456 NMFSINAMG 1636 TLISWSSGRTSYA 1816 CASLGYCSGGSCFDYW 6-46 1457 LTFSAMG 1637 ALIRRDGSTIYA 1817 CAALGILFGYDAFDIW 6-47 1458 RTFSMHAMG 1638 ASITYGGNINYA 1818 CAKEGYYDSTGYRTYFQQW 6-48 1459 FTVSNYAMG 1639 ASVNWSGGTTSYA 1819 CATTGTVTLGYW 6-49 1460 STVLINAMG 1640 AAISWSPGRTDYA 1820 CARDCSGGSCYSGDYW 6-50 1461 FSFDRWAMG 1641 ASLATGGNTNYA 1821 CARVTNYDAFDIW 6-51 1462 YTYSSYVMG 1642 AAISRFGSTYYA 1822 CARDSGEHFWDSGYIDHW 6-52 1463 DTYGSYWMG 1643 AAITSGGSTVYA 1823 CARVDSRFDYW 6-53 1464 ISINTNVMG 1644 AAISTGSVTIYA 1824 CARVDDFGYFDLW 6-54 1465 FEFENHWMG 1645 AHITAGGLSNYA 1825 CGRHWGIYDSSGFSSFDYW 6-55 1466 FTMSSSWMG 1646 ARITSGGSTGYA 1826 CASVDGYFDYW 6-56 1467 NIFRSNMG 1647 AGITWNGDTTYYA 1827 CARALGVTYQFDYW 6-57 1468 LTFDDHSMG 1648 AAVPLSGNTYYA 1828 CASFSGGPADFDYW 6-58 1469 RAVSTYAMG 1649 AAISGSENVTSYA 1829 CLSVTGDTEDYGVFDTW 6-59 1470 ISGSVFSRTPM 1650 SSIYSDGSNTYYA 1830 CAHWSWELGDWFDPW G 6-60 1471 DTYGSYWMG 1651 ATISQSGAATAYA 1831 CAGLLRYSGTYYDAFDVW 6-61 1472 DTYGSYWMG 1652 AAINWSGGSTNYA 1832 CAGLGWNYMDYW 6-62 1473 STFSGNWMG 1653 AVISWTGGSTYYA 1833 CATHNSLSGFDYW 6-63 1474 QTFNMG 1654 AAIGSGGSTSYA 1834 CWRLGNDYFDYW 6-64 1475 IPSIHAMG 1655 AAINWSHGVTYYA 1835 CGGGYGYHFDYW 6-65 1476 LPFSTLHMG 1656 ASLSIFGATGYA 1836 CWMYYYDSSGYYGNYY YGMDVW 6-66 1477 LTFSLFAMG 1657 AAISSGGSTDYA 1837 CARGNTKYYYDSSGYSS AFDYW 6-67 1478 SFSNYAMG 1658 AAISSSGALTSYA 1838 CWIVGPGPLDGMDVW 6-68 1479 FTLSDRAMG 1659 AHITAGGLSNYA 1839 CVHLASQTGAGYFDLW 6-69 1480 GTFSSVGMG 1660 AGISRSGGTYYA 1840 CARYDFWSGYPYW 6-70 1481 FNLDDYADM 1661 AAIGWGGGSTRYA 1841 CAREILWFGEFGEPNVW G 6-71 1482 ITFSNDAMG 1662 AIITSSDTNDTTNYA 1842 CARLHYYDSSGYFDYW 6-72 1483 STLSINAMG 1663 AAIDWSGGSTAYA 1843 CARDSSATRTGPDYW 6-73 1484 HTFSGYAMG 1664 AVITREGSTYYA 1844 CARLGGEGFDYW 6-74 1485 FAFGDSWMG 1665 AAITSGGSTDYA 1845 CARGLLWFGELFGYW 6-75 I486 GTFSTYWMG 1666 AAISRSGGNTYYA 1846 CVRHSGTDGDSSFDYW 6-76 1487 LAFDFDGMG 1667 AAINSGGSTYYA 1847 CARFFRAHDYW 6-77 1488 FTFDRSWMG 1668 AAVTEGGTTSYA 1848 C'ARADYDFDYW 6-78 1489 RTYDAMG 1669 ASVTSGGYTHYA 1849 CAKFGRKIVGATELDYW 6-79 1490 SISSIDYMG 1670 SWISSSDGSTYYA 1850 CARSPSFSQIYYYYY MDVW 6-80 1491 GTFSFYNMG 1671 AFISGNGGTSYA 1851 CAVVAMRMVTTEGPDV LDVW 6-81 1492 FIGNYHAMG 1672 AAVTWSGGTTNYA 1852 CAREGYYYDSSGYPYY FDYW 6-82 1493 SSLDAYGMG 1673 AAISWGGGSIYYA 1853 CARLSQGMVALDYW 6-83 1494 SIASIHAMG 1674 AAITWSGAITSYA 1854 CAKDGGYGELHYGMEVW 6-84 1495 FTPDDYAMG 1675 AAINSGGSYTYYA 1855 CARDRGPW 6-85 1496 GTFSVFAMG 1676 SAINWSGGSLLYA 1856 CALFGDFDYW 6-86 1497 PISGINRMG 1677 AVITSNGRPSYA 1857 CVRLSSGYFDFDYW 6-87 1498 TSIMVGAMG 1678 AIIRGDGRTSYA 1858 CARFAGWDAFDIW 6-88 1499 RTFSTHWMG 1679 AVINWSGGSIYYA 1859 CARLSSDGYNYFDFW 6-89 1500 TIFASAMG 1680 AVVNWNGSSTVYA 1860 CTTVDQYFNYW 6-90 1501 FPFSIWPMG 1681 AAVRWSSTYYA 1861 CATGECDGGSCSLAYW 6-91 1502 RTFGNYAMG 1682 ASISSSGVSKHYA 1862 CVRFGSSWARDLDQW 6-92 1503 FLFDSYASMG 1683 ATIWRRGNTYYANY 1863 CTETGTAAW A 6-93 1504 LPFSTKSMG 1684 AAISMSGLTSYA 1864 CLKVLGGDYEADNWFDYW 6-94 1505 NIFRIETMG 1685 AGIIRSGGETLYA 1865 CARSLYYDRSGSYYFDYW 6-95 1506 IPSSIRAMG 1686 AVIRWTGGSTYYA 1866 CARDIGYYDSSGYYNDG GFDYW 6-96 1507 FTLSGNWMG 1687 AIITSGGRTNYA 1867 CAGHATFGGSSSSYYYG MDVW 6-97 1508 FTFSSLAMG 1688 AAITWSGDITNYA 1868 CLRLSSSGFDHW 6-98 1509 TFGHYAMG 1689 AAINWSSRSTVYA 1869 CAKSDGLMGELRSAS AFDIW 6-99 1510 IPFRSRTMG 1690 AGISRSGASTAYA 1870 CTHANDYGDYW 6-100 1511 GTFSTSWMG 1691 AHITAGGLSNYA 1871 CARLLVREDWYFDLW 6-101 1512 GTFSLFAMG 1692 AAISWTGDSTYYKY 1872 CAYNNSSGEYW YA 6-102 1513 SSFSAYAMG 1693 SAIDSEGTTTYA 1873 CAGDYNFWSGFDHW 6-103 1514 RTSSPIAMG 1694 AVRWSDDYTYYA 1874 CAKKLGGYYAFDIW 6-104 1515 LTFNQYTMG 1695 ASITDGGSTYYA 1875 CARDSRYMDVW 6-105 1516 PTFSSMG 1696 AAISWDGGATAYA 1876 CAIEIVVGGIYW 6-106 1517 IPSTLRAMG 1697 AATSWSGGSKYYA 1877 CATDLYYMDVW 6-107 1518 GVGFSVTNM 1698 AVISSSSSTNYA 1878 CTTFNWNDEGFDYW G 6-108 1519 GTFGSYGMG 1699 AAIRWSGGITYYA 1879 CARERYWNPLPYYYYGMD VW 6-109 1520 GTFSTYAMG 1700 ASIDWSGLTSYA 1880 CARGPFYMYCSGTKCYSTN WFDPW 6-110 1521 PIYAVNRMG 1701 AGIWRSGGHRDYA 1881 CARGEIDILTGYWYDYW 6-111 1522 FTFSNYWMG 1702 GGISRSGVSTSYA 1882 CTTLLYYYDSSGYSFDAFDI W 6-112 1523 GTFSAYHMG 1703 TIIDNGGPTSYA 1883 CTALLYYFDNSGYNFDPFDI W 

TABLE 35 SARS-CoV-2 S1 Variant Variably Heavy Chain SEQ Name ID NO Amino Acid Sequence 5-1 1884 EVQLVESGGGLVQPGGSLRLSCAASGGTFSSIGMGWFRQAPGKEREFVAAISWD GGATAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKEDVGKPFDW GQGTLVTVSS 5-2 1885 EVQLVESGGGLVQPGGSLRLSCAASGLRFDDYAMGWFRQAPGKERELVAIKFSG GTTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASWDGLIGLDAYE YDWGQGTLVTVSS 5-3 1886 EVQLVESGGGLVQPGGSLRLSCAASGSIFSIDVMGWFRQAPGKEREFVAGISWSG DSTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAFDGYTGSDWG QGTLVTVSS 5-4 1887 EVQLVESGGGLVQPGGSLRLSCAASGFTLADYAMGWFRQAPGKEREFVAVITCS GGSTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADDCYIGCGW GQGTLVTVSS 5-5 1888 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSIAMGWFRQAPGKERELVAEITEGG ISPSGDNIYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAELHSSDY TSPGAESDYGWGQGTLVTVSS 5-6 1889 EVQLVESGGGLVQPGGSLRLSCAASGPTFSSYAMMGWFRQAPGKEREWVAAIN NFGTTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAASASDYGLGL ELFHDEYNWGQGTLVTVSS 5-7 1890 EVQLVESGGGLVQPGGSLRLSCAASGSTGYMGWFRQAPGKEREFVAAIHSGGST NYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATVATALIWGQGTLVT VSS 5-8 1891 EVQLVESGGGLVQPGGSLRLSCAASGRPFSEYTMGWFRQAPGKEREFVSSIHWG GRGTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAELHSSDYTSP GAYAWGQGTLVTVSS 5-9 1892 EVQLVESGGGLVQPGGSLRLSCAASGLTLSTYGMGWFRQAPGKEREFVAHIPRST YSPYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAIGDGAVWGQG TLVTVSS 5-10 1893 EVQLVESGGGLVQPGGSLRLSCAASGFTFNNHNMGWFRQAPGKEREFVAAISSY SHTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCALQPFGASNYRW GQGTLVTVSS 5-11 1894 EVQLVESGGGLVQPGGSLRLSCAASGGIYRVMGWFRQAPGKERELVASISSGGGI NYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAESWGRQWGQGTLV TVSS 5-12 1895 EVQLVESGGGLVQPGGSLRLSCAASGYTDSNLWMGWFRQAPGKEREFVAINRST GSTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATSGSGSPNWGQG TLVTVSS 5-13 1896 EVQLVESGGGLVQPGGSLRLSCAASGFTFDYYTMGWFRQAPGKEREFVAAIRSS GGLFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAYLDGYSGSWG QGTLVTVSS 5-14 1897 EVQLVESGGGLVQPGGSLRLSCAASGGIFSINVMGWFRQAPGKEREWVSAIRWN GGNTAYADSVKGRFTITADNSKNTAYLQMNSLKPEDTAVYYCAGFDGYTGSDW GQGTLVTVSS 5-15 1898 EVQLVESGGGLVQPGGSLRLSCAASGFTFDGAAMGWFRQAPGKEREFVATIRWT NSTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGRYGIVERWG QGTLVTVSS 5-16 1899 EVQLVESGGGLVQPGGSLRLSCAASGRTHSIYPMGWFRQAPGKERELVAAIHSG GATVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARRWIPPGPIWG QGTLVTVSS 5-17 1900 EVQLVESGGGLVQPGGSLRLSCAASGPTFSIYAMGWFRQAPGKEREFVAGIRWS DVYTQYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCALDIDYRDWGQ GTLVTVSS 5-18 1901 EVQLVESGGGLVQPGGSLRLSCAASGLTFDDNIHVMGWFPQAPGKEREFVAAIH WSGGSTIYADSVKGRFTINADNSKNTAYLQMNSLKPEDTAVYYCAADVYPQDY GLGYVEGKMYYGMDWGQGTLVTVSS 5-19 1902 EVQLVESGGGLVQPGGSLRLSCAASGLTLDYYAMGWFRQAPGKEREWVASINW SGGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAYGSGEFDW GQGTLVTVSS 5-20 1903 EVQLVESGGGLVQPGGSLRLSCAASGRTIVPYTMGWFRQAPGKERELVAAISPSA FTEYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARRWGYDWGQGT LVTVSS 5-21 1904 EVQLVESGGGLVQPGGSLRLSCAASGGTFTTYHMGWFRQAPGKEREFVAHISTG GATNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATFPAIVTDSDYD LGNDWGQGTLVTVSS 5-22 1905 EVQLVESGGGLVQPGGSLRLSCAASGFTFNVFAMGWFRQAPGKEREFVAAINWS DSRTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASGSDNRARELS RYEYVWGQGTLVTVSS 5-23 1906 EVQLVESGGGLVQPGGSLRLSCAASGSIFSIDVMGWFRQAPGKEREFVAAISWSG ESTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAFDGYSGSDWGQ GTLVTVSS 5-24 1907 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMGWFRQAPGKEREFVAAISSYS HTAYADSVKGRFTIIADNSKNTAYLQMNSLKPEDTAVYYCALQPFGASSYRWGQ GTLVTVSS 5-25 1908 EVQLVESGGGLVQPGGSLRLSCAASGNTFSINVMGWFRQAPGKEREFVAAIHWS GDSTLYADSGKGRFTIIADNNKNTAYLQMISLKPEDTAVYYCAAFDGYSGNHWG QGTLVTVSS 5-26 1909 EVQLVESGGGLVQPGGSLRLSCAASGRTISSYIMGWFRQAPGKERELVARIYTGG DTIYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARTSYNGRYDYID DYSWGQGTLVTVSS 5-27 1910 EVQLVESGGGLVQPGGSLRLSCAASGRANSINWMGWFRQAPGKEREFVATITPG GNTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAAAGSTWYGTL YEYDWGQGTLVTVSS 5-28 1911 EVQLVESGGGLVQPGGSLRLSCAASGGTFSVFAMGWFRQVPGKERELVAEITAG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVDGPFGWGQGT LVTVSS 5-29 1912 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYPMGWFRQAPGKEREGVASVLRG GYTWYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKDWATGLAWG QGTLVTVSS 5-30 1913 EVQLVESGGGLVQPGGSLRLSCAASGFALGYYAMGWFRQAPGKEREFVAGIRW TDAYTEYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADVSPSYGSR WYWGQGTLVTVSS 5-31 1914 EVQLVESGGGLVQPGGSLRLSCAASGRTLDIHVMGWFRQAPGKEREFVAVINWT GESTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAFDGYTGNYW GQGTLVTVSS 5-32 1915 EVQLVESGGGLVQPGGSLRLSCAASGFTPDNYAMGWFRQAPGKEREFVAALGW SGVTTYHYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASDESDAAN WGQGTLVTVSS 5-33 1916 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYAMGWFRQAPGKERELVATIMW SGNTTYYADSVRRRFIIRDNNNKNTAHLQMNSLKPEDTAVYYCATNDDDVWGQ GTLVTVSS 5-34 1917 EVQLVESGGGLVQPGGSLRLSCAASGRTFSRYIMGWFRQAPGKEREFVAAISWSG GDNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAYRIWGGTSP GDWRWGQGTLVTVSS 5-35 1918 EVQLVESGGGLVQPGGSLRLSCAASGPTFSIYAMGWFRQAPGKERELVAGISWN GGSTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCALRRRFGGQEW GQGTLVTVSS 5-36 1919 EVQLVESGGGLVQPGGSLRLSCAASGRTFSLNAMGWFRQAPGKERELVAAISCG GGSTYADNGKGRFTIITDNSKNTAYLQMMNLKPEDTAAYYCAADNDMGYCSW GQGTLVTVSS 5-37 1920 EVQLVESGGGLVQPGGSLRLSCAASGSTFSINAMGWFRQAPGKEREFVGGISRSG ATTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADGVPEYSDYAS GPVWGQGTLVTVSS 5-38 1921 EVQLVESGGGLVQPGGSLRLSCAASGRTFSMHAMGWFRQAPGKERELVASISSQ GRTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAEVRNGSDYLPI DWGQGTLVTVSS 5-39 1922 EVQLVESGGGLVQPGGSLRLSCAASGVTLDLYAMGWFRQAPGKEREFVAGIRW TDAYTEYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVDIDYRDWG QGTLVTVSS 5-40 1923 EVQLVESGGGLVQPGGSLRLSCAASGLPFTINVMGWFRQAPGKEREFVAAIHWS GLTTFYADSVKGLFTITEDNSKNTAHLMMNLLKPEDTAVYCCAELDGYFFAHWG QGTLVTVSS 5-41 1924 EVQLVESGGGLVQPGGSLRLSCAASGRAFSNYAMGWFRQAPGKEREFVAWINN RGTTDYADSGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASTD DYGVDWGQGTLVTVSS 5-42 1925 EVQLVESGGGLVQPGGSLRLSCAASGFTPDDYAMGWFRQAPGKEREFVASIGYS GRSNSYNYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAIAHGSSTY NWGQGTLVTVSS 5-43 1926 EVQLVESGGGLVQPGGSLRLSCAASGFTLNYYGMGWFPQAPGKEREFVAAITSG GAPHYADSVKGRFTINADNSKNTAYLQMNSLKPEDTAVYYCASAYDRGIGYDW GQGTLVTVSS 5-44 1927 EVQLVESGGGLVQPGGSLRLSCAASGLPFSTKSMGWFRQAPGKEREFVAAIHWS GLTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRAADFFAQRD EYDWGQGTLVTVSS 5-45 1928 EVQLVESGGGLVQPGGSLRLSCAASGRTFSINAMGWFPQAPGKERELVAAISWSG ESTQYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAFDGGSGTQWG QGTLVTVSS 5-46 1929 EVQLVESGGGLVQPGGSLRLSCAASGEEFSDHWMGWFRQAPGKEREFVAAIHW SGDSTHRNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATVGITLNW GQGTLVTVSS 5-47 1930 EVQLVESGGGLVQPGGSLRLSCAASGFTFGSYDMGWFRQAPGKEREFVTAINWS GARTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARSVYSYEYN WGQGTLVTVSS 5-48 1931 EVQLVESGGGLVQPGGSLRLSCAASGLPLDLYAMGWFPPAPGKELEFVAGIRWS DAYTEYADSVKGRFTINADNSKNPANLQMNSLKPEDTAVYYCALDIDYRHWGQ GTLVTVSS 5-49 1932 EVQLVESGGGLVQPGGSLRLSCAASGRTSTVNGMGWFRQAPGKEREFVASISQS GAATAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRTYSYSSTG YYWGQGTLVTVSS 5-50 1933 EVQLVESGGGLVQPGGSLRLSCAASGFSLDYYGMGWFRQAPGKEREFVAAITSG GTPHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASAYNPGIGYDWG QGTLVTVSS 5-51 1934 EVQLVESGGGLVQPGGSLRLSCAASGRPNSINWMGWFRQAPGKERQFVATITPG GNTNYADSVKGRFTISADNSKNTAYLLMNSLKPEDTAVYYCAAAAGTTWYGTL YEYDWGQGTLVTVSS 5-52 1935 EVQLVESGGGLVQPGGSLRLSCAASGEKFSDHWMGWFRQAPGKEREFVATITFS GARTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAALIKPSSTDRIF EEWGQGTLVTVSS 5-53 1936 EVQLVESGGGLVQPGGSLRLSCAASGLTVVPYAMGWFRQAPGKEREFVAAIRRS AVTNYADSVKGRFTIIADNSKNTAYLLMNSLKPEDTAVYYCAARRWGYHYWGQ GTLVTVSS 5-54 1937 EVQLVESGGGLVQPGGSLRLSCAASGTTFNFNVMGWFRQAPGKERELVAVISWT GESTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAFDGYTGRDW GQGTLVTVSS 5-55 1938 EVQLVESGGGLVQPGGSLRLSCAASGIDVNRNAMGWFRQAPGKEREFVAAITWS GGWRYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTFGDAGIPDQ YDFGWGQGTLVTVSS 5-56 1939 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSNMGWFRQAPGKEREFVARIFGGD RTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCADINGDWGQGTLVT VSS 5-57 1940 EVQLVESGGGLVQPGGSLRLSCAASGGTFSMGWIRWVPQAQGKELEFMGCIGWI TYYADYAKSRFSLFTDNADNTKNPPNMHMNPQKPEDTAVYYCAPFGWGQGTLV TVSS 5-58 1941 EVQLVESGGGLVQPGGSLRLSCAASGCTLDYYAMGWFRQAPGKEREFVAGIRW TDAYTEYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADVSPSYGGR WYWGQGTLVTVSS 5-59 1942 EVQLVESGGGLVQPGGSLRLSCAASGLTFSLYRMCWFRQAPGKEREEVSCISNID GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADLLGDSDYEPS SGFGWGQGTLVTVSS 5-60 1943 EVQLVESGGGLVQPGGSLRLSCAASGRSFSSHRMGWFRQAPGKEREFVAAIMWS GSHRNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAIAYEEGVYR WDWGQGTLVTVSS 5-61 1944 EVQLVESGGGLVQPGGSLRLSCAASGRIIVPNTMGWFRQAPGKERERVTGISPSAF TEYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAHGWGCHWGQGTL VTVSS 5-62 1945 EVQLVESGGGLVQPGGSLRLSCAASGSIFIISMGWFRQAPGKEHEFVTGINWSGGS TTYADSVKGRFTINADNSKNTAYLQMNSLKPEDTAVYYCAASAIGSGALRRFEY DWGQGTLVTVSS 5-63 1946 EVQLVESGGGLVQPGGSLRLSCAASGFSLDYYDMGWFRQAPGKEREFVAALGW SGGSTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAGNGGRYGIV ERWGQGTLVTVSS 5-64 1947 EVQLVESGGGLVQPGGSLRLSCAASGTSISNRVMGWFRQAPGKERELVARIYTG GDTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARKIYRSLSYYG DYDWGQGTLVTVSS 5-65 1948 EVQLVESGGGLVQPGGSLRLSCAASGNIDRLYAMGWFRQAPGKEREGVAAIDSD GSTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAALIDYGLGFPIEW GQGTLVTVSS 5-66 1949 EVQLVESGGGLVQPGGSLRLSCAASGNTFTINVMGWFRQAPGKEREFVAAINWN GGTTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAFDGYSGIDWG QGTLVTVSS 5-67 1950 EVQLVESGGGLVQPGGSLRLSCAASGFNVNDYAMGWFRQAPGKEREFVAGITSS VGVTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADIFFVNWGR GTLVTVSS 5-68 1951 EVQLVESGGGLVQPGGSLRLSCAASGFTFDHYTMGWFRQAPGKEREFVAAISGS ENVTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAEPYIPVRTMR HMTFLTWGQGTLVTVSS 6-1 1952 EVQLVESGGGLVQPGGSLRLSCAASGRTFGNYNMGWFRQAPGKEREFVATINSL GGTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVDYYMDVWG QGTLVTVSS 6-2 1953 EVQLVESGGGLVQPGGSLRLSCAASGFTMSSSWMGWFRQAPGKEREFVTVISGV GTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGPDSSGYGFDYW GQGTLVTVSS 6-3 1954 EVQLVESGGGLVQPGGSLRLSCAASGFTFSPSWMGWFRQAPGKEREFVATINEY GGRNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVDRDFDYWGQ GTLVTVSS 6-4 1955 EVQLVESGGGLVQPGGSLRLSCAASGFTRDYYTMGWFRQAPGKEREFVAAISRS GSLTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCANLAYYDSSGYY DYWGQGTLVTVSS 6-5 1956 EVQLVESGGGLVQPGGSLRLSCAASGRTFTMGWFRQAPGKEREFVASTNSAGST NYADSVNGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTTVDQYFDYWGQGTL VTVSS 6-6 1957 EVQLVESGGGLVQPGGSLRLSCAASGTTLDYYAMGWFRQAPGKERELVAAISWS GGSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAREDYYDSSGYS WGQGTLVTVSS 6-7 1958 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMGWFRQAPGKEREFVATINWS GVTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARADDYFDYWGQ GTLVTVSS 6-8 1959 EVQLVESGGGLVQPGGSLRLSCAASGFTLSGIWMGWFLQAPGKEHEFVAIITTGG RTTYADSXKGRFTSSSDNSKNTAYLQMNLLKPEDTAEYYCAGYSTFGSSSAYYY YSMDVGWGQGTLVTVSS 6-9 1960 EVQLVESGGGLVQPGGSLRLSCAASGFTFDYYAMGWFRQAPGKEREFVSAIDSE GRTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARWGPFDIWGQGT LVTVSS 6-10 1961 EVQLVESGGGLVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAAISRSG GFGSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDDKYYDSSGYP AYFQHWGQGTLVTVSS 6-11 1962 EVQLVESGGGLVQPGGSLRLSCAASGLAFNAYAMGWFRQAPGKEREEVATIGW SGANTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASDPPGWGQG TLVTVSS 6-12 1963 EVQLVESGGGLVQPGGSLRLSCAASGSTYTTYSMGWFRQAPGKEREFVAAISGSE NVTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVDDYMDVWG QGTLVTVSS 6-13 1964 EVQLVESGGGLVQPGGSLRLSCAASGLTFNDYAMGWFRQAPGKEREFVAHIPRS TYSPYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAFLVGPQGVDHG AFDVWGQGTLVTVSS 6-14 1965 EVQLVESGGGLVQPGGSLRLSCAASGITFRFKAMGWFRQAPGKEREFVAAVSWD GRNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASDYYYMDVW GQGTLVTVSS 6-15 1966 EVQLVESGGGLVQPGGSLRLSCAASGSTVLINAMGWFRQAPGKEREFVAAVRWS DDYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKEGRAGSLDY WGQGTLVTVSS 6-16 1967 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDAAMGWFRQAPGKEREFVAHISWS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATFGATVTATND AFDIWGQGTLVTVSS 6-17 1968 EVQLVESGGGLVQPGGSLRLSCAASGNTGSTGYMGWFRQAPGKEREMVAGVIN DGSTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARLATSHQDGTG YLFDYWGQGTLVTVSS 6-18 1969 EVQLVESGGGLVQPGGSLRLSCAASGLTFRNYAMGWFRQAPGKEREFIAGMMW SGGTTTYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAREGYYYDSSG YLNYFDYWGQGTLVTVSS 6-19 1970 EVQLVESGGGLVQPGGSLRLSCAASGSILSIAVMGWFRQAPGKEREFVAAISPSA VTTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAIGYYDSSGYFDY WGQGTLVTVSS 6-20 1971 EVQLVESGGGLVQPGGSLRLSCAASGSTLPYHAMGWFRQAPGKEREFVAAITWN GASTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDRYYDTSASY FESETWGQGTLVTVSS 6-21 1972 EVQLVESGGGLVQPGGSLRLSCAASGTLFKINAMGWFRQAPGKEREFVAAITSSG SNIDYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARSNTGWYSF DYWGQGTLVTVSS 6-22 1973 EVQLVESGGGLVQPGGSLRLSCAASGRTFSEVVMGWFRQAPGKEREFVATIHSSG STSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCVRVTSDYSMDSWG QGTLVTVSS 6-23 1974 EVQLVESGGGLVQPGGSLRLSCAASGSIFSMNTMGWFRQAPGKEREFVALINRSG GGINYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCVRLSSGYYDFDYW GQGTLVTVSS 6-24 1975 EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAMGWFRQAPGKEREFVAAINWS GDNTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARAPFYCTTTKC QDNYYYMDVWGQGTLVTVSS 6-25 1976 EVQLVESGGGLVQPGGSLRLSCAASGLTFGTYTMGWFRQAPGKEREFVAAISRF GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGGDYDFWSVD YMDVWGQGTLVTVSS 6-26 1977 EVQLVESGGGLVQPGGSLRLSCAASGDTFSTSWMGWFRQAPGKEREFVATINTG GGTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVTTSFDYWGQ GTLVTVSS 6-27 1978 EVQLVESGGGLVQPGGSLRLSCAASGITFRFKAMGWFRQAPGKEREFVASISRSG TTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDYSAFDMWGQG TLVTVSS 6-28 1979 EVQLVESGGGLVQPGGSLRLSCAASGDTYGSYWMGWFRQAPGKEREFVATITSD DRTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVTSSLSGMDV WGQGTLVTVSS 6-29 1980 EVQLVESGGGLVQPGGSLRLSCAASGYTLKNYYAMGWFRQAPGKERXLVAAII WTGESTLDADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAREGYYDSSG YYWGQGTLVTVSS 6-30 1981 EVQLVESGGGLVQPGGSLRLSCAASGFAFGDSWMGWFRQAPGKEREFVATINWS GVTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARADGYFDYWGQ GTLVTVSS 6-31 1982 EVQLVESGGGLVQPGGSLRLSCAASGDTFSANRMGWFRQAPGKEREFVASITWS SANTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATFNWNDEGFDF WGQGTLVTVSS 6-32 1983 EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYDMGWFRQAPGKEREFVALISWS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDFYGWGTRE RDAFDIWGQGTLVTVSS 6-33 1984 EVQLVESGGGLVQPGGSLRLSCAASGTFQRINHMGWFRQAPGKEREFVATINTG GQPNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASLIAAQDYYFDY WGQGTLVTVSS 6-34 1985 EVQLVESGGGLVQPGGSLRLSCAASGSAFRSNAMGWFRQAPGKEREFVAHISWS SKSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATYCSSTSCFDY WGQGTLVTVSS 6-35 1986 EVQLVESGGGLVQPGGSLRLSCAASGFTLAYYAMGWFRQAPGKEREFVAAISMS GDDTIYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARELGYSSTVWP WGQGTLVTVSS 6-36 1987 EVQLVESGGGLVQPGGSLRLSCAASGFDFSVSWMGWFRQAPGKEREFVTAITWS GDSTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASLLHTGPSGGN YFDYWGQGTLVTVSS 6-37 1988 EVQLVESGGGLVQPGGSLRLSCAASGHTFSTSWMGWFRQAPGKEREFVATINSL GGTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVSSGDYGMDV WGQGTLVTVSS 6-38 1989 EVQLVESGGGLVQPGGSLRLSCAASGNTFSGGFMGWFRQAPGKEREFVAVISSLS SKSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKVDSGYDYWGQG TLVTVSS 6-39 1990 EVQLVESGGGLVQPGGSLRLSCAASGFTFSPSWMGWFRQAPGKEREFVAAISWS GGSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCHGLGEGDPYGD YEGYFDLWGQGTLVTVSS 6-40 1991 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYWMGWFRQAPGKERELVARVW WNGGSAYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAREVLRQQV VLDYWGQGTLVTVSS 6-41 1992 EVQLVESGGGLVQPGGSLRLSCAASGFTFSTSWMGWFRQAPGKEREFVASINEY GGRNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAGLHYYYDSSGY NPTEYYGMDVWGQGTLVTVSS 6-42 1993 EVQLVESGGGLVQPGGSLRLSCAASGDTYGSYWMGWFRQAPGKEREFVAVITSG GSTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTHVQNSYYYAMD VWGQGTLVTVSS 6-43 1994 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSYAMMGWFRQAPGKEREFVASVN WDASQINYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTTLGAVYFDS SGYHDYFDYWGQGTLVTVSS 6-44 1995 EVQLVESGGGLVQPGGSLRLSCAASGGTFGVYHMGWFRQAPGKEREFIGRITWT DGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCFGLLEVYDMTFD YWGQGTLVTVSS 6-45 1996 EVQLVESGGGLVQPGGSLRLSCAASGNMFSINAMGWFRQAPGKEREFVTLISWSS GRTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASLGYCSGGSCFD YWGQGTLVTVSS 6-46 1997 EVQLVESGGGLVQPGGSLRLSCAASGLTFSAMGWFRQAPGKEREFVALIRRDGST IYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAALGILFGYDAFDIWGQ GTLVTVSS 6-47 1998 EVQLVESGGGLVQPGGSLRLSCAASGRTFSMHAMGWFRQAPGKERELVASITYG GNINYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKEGYYDSTGYRT YFQQWGQGTLVTVSS 6-48 1999 EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYAMGWFRQAPGKEREFVASVNW SGGTTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTGTVTLGYW GQGTLVTVSS 6-49 2000 EVQLVESGGGLVQPGGSLRLSCAASGSTVLINAMGWFRQAPGKEREFVAAISWSP GRTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDCSGGSCYSGD YWGQGTLVTVSS 6-50 2001 EVQLVESGGGLVQPGGSLRLSCAASGFSFDRWAMGWFRQAPGKEREWVASLAT GGNTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVTNYDAFDI WGQGTLVTVSS 6-51 2002 EVQLVESGGGLVQPGGSLRLSCAASGYTYSSYVMGWFRQAPGKEREFVAAISRF GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDSGEHFWDSG YIDHWGQGTLVTVSS 6-52 2003 EVQLVESGGGLVQPGGSLRLSCAASGDTYGSYWMGWFRQAPGKEREVVAAITS GGSTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVDSRFDYWG QGTLVTVSS 6-53 2004 EVQLVESGGGLVQPGGSLRLSCAASGISINTNVMGWFRQAPGKEREFVAAISTGS VTIYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVDDFGYFDLWGQ GTLVTVSS 6-54 2005 EVQLVESGGGLVQPGGSLRLSCAASGFEFENHWMGWFRQAPGKEREYVAHITA GGLSNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCGRHWGIYDSSGF SSFDYWGQGTLVTVSS 6-55 2006 EVQLVESGGGLVQPGGSLRLSCAASGFTMSSSWMGWFRQAPGKEREFVARITSG GSTGYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASVDGYFDYWGQ GTLVTVSS 6-56 2007 EVQLVESGGGLVQPGGSLRLSCAASGNIFRSNMGWFRQAPGKEREFVAGITWNG DTTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARALGVTYQFDY WGQGTLVTVSS 6-57 2008 EVQLVESGGGLVQPGGSLRLSCAASGLTFDDHSMGWFRQAPGKEREFVAAVPLS GNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASFSGGPADFDY WGQGTLVTVSS 6-58 2009 EVQLVESGGGLVQPGGSLRLSCAASGRAVSTYAMGWFRQAPGKEREFVAAISGS ENVTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCLSVTGDTEDYGV FDTWGQGTLVTVSS 6-59 2010 EVQLVESGGGLVQPGGSLRLSCAASGISGSVFSRTPMGWFRQAPGKEREWVSSIY SDGSNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAHWSWELGD WFDPWGQGTLVTVSS 6-60 2011 EVQLVESGGGLVQPGGSLRLSCAASGDTYGSYWMGWFRQAPGKEREFVATISQS GAATAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAGLLRYSGTYY DAFDVWGQGTLVTVSS 6-61 2012 EVQLVESGGGLVQPGGSLRLSCAASGDTYGSYWMGWFRQAPGKEREFVAAINW SGGSTNYADSVKGRFTITADNNKNTAYLQMNSLKPEDTAVYYCAGLGWNYMD YWGQGTLVTVSS 6-62 2013 EVQLVESGGGLVQPGGSLRLSCAASGSTFSGNWMGWFRQAPGKEREFVAVISWT GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATHNSLSGFDYW GQGTLVTVSS 6-63 2014 EVQLVESGGGLVQPGGSLRLSCAASGQTFNMGWFRQAPGKEREFVAAIGSGGST SYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCWRLGNDYFDYWGQGT LVTVSS 6-64 2015 EVQLVESGGGLVQPGGSLRLSCAASGIPSIHAMGWFRQAPGKERELVAAINWSH GVTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCGGGYGYHFDYWG QGTLVTVSS 6-65 2016 EVQLVESGGGLVQPGGSLRLSCAASGLPFSTLHMGWFRQAPGKEREFVASLSIFG ATGYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCWMYYYDSSGYYGN YYYGMDVWGQGTLVTVSS 6-66 2017 EVQLVESGGGLVQPGGSLRLSCAASGLTFSLFAMGWFRQAPGKERELVAAISSGG STDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGNTKYYYDSSGY SSAFDYWGQGTLVTVSS 6-67 2018 EVQLVESGGGLVQPGGSLRLSCAASGSFSNYAMGWFRQAPGKEREFVAAISSSG ALTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCWIVGPGPLDGMDV WGQGTLVTVSS 6-68 2019 EVQLVESGGGLVQPGGSLRLSCAASGFTLSDRAMGWFRQAPGKEREYVAHITAG GLSNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCVHLASQTGAGYFD LWGQGTLVTVSS 6-69 2020 EVQLVESGGGLVQPGGSLRLSCAASGGTFSSVGMGWFRQAPGKEREFVAGISRS GGTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARYDFWSGYPYW GQGTLVTVSS 6-70 2021 EVQLVESGGGLVQPGGSLRLSCAASGFNLDDYADMGWFRQAPGKEREFVAAIG WGGGSTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAREILWFGEF GEPNVWGQGTLVTVSS 6-71 2022 EVQLVESGGGLVQPGGSLRLSCAASGITFSNDAMGWFRQAPGKEREFVAIITSSDT NDTTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARLHYYDSSGYF DYWGQGTLVTVSS 6-72 2023 EVQLVESGGGLVQPGGSLRLSCAASGSTLSINAMGWFRQAPGKEREFVAAIDWS GGSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDSSATRTGPD YWGQGTLVTVSS 6-73 2024 EVQLVESGGGLVQPGGSLRLSCAASGHTFSGYAMGWFRQAPGKEREFVAVITRE GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARLGGEGFDYWG QGTLVTVSS 6-74 2025 EVQLVESGGGLVQPGGSLRLSCAASGFAFGDSWMGWFRQAPGKERELVAAITSG GSTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGLLWFGELFGY WGQGTLVTVSS 6-75 2026 EVQLVESGGGLVQPGGSLRLSCAASGGTFSTYWMGWFRQAPGKEREFVAAISRS GGNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCVRHSGTDGDSSF DYWGQGTLVTVSS 6-76 2027 EVQLVESGGGLVQPGGSLRLSCAASGLAFDFDGMGWFRQAPGKEREGVAAINSG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARFFRAHDYWGQ GTLVTVSS 6-77 2028 EVQLVESGGGLVQPGGSLRLSCAASGFTFDRSWMGWFRQAPGKEREFVAAVTE GGTTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARADYDFDYWG QGTLVTVSS 6-78 2029 EVQLVESGGGLVQPGGSLRLSCAASGRTYDAMGWFRQAPGKEREFVASVTSGG YTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKFGRKIVGATELD YWGQGTLVTVSS 6-79 2030 EVQLVESGGGLVQPGGSLRLSCAASGSISSIDYMGWFRQAPGKEREGVSWISSSD GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARSPSFSQIYYYYY MDVWGQGTLVTVSS 6-80 2031 EVQLVESGGGLVQPGGSLRLSCAASGGTFSFYNMGWFRQAPGKEREFVAFISGN GGTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVVAMRMVTTEG PDVLDVWGQGTLVTVSS 6-81 2032 EVQLVESGGGLVQPGGSLRLSCAASGFIGNYHAMGWFRQAPGKEREFVAAVTW SGGTTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAREGYYYDSSG YPYYFDYWGQGTLVTVSS 6-82 2033 EVQLVESGGGLVQPGGSLRLSCAASGSSLDAYGMGWFRQAPGKEREFVAAISWG GGSIYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARLSQGMVALDY WGQGTLVTVSS 6-83 2034 EVQLVESGGGLVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAAITWSG AITSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKDGGYGELHYG MEVWGQGTLVTVSS 6-84 2035 EVQLVESGGGLVQPGGSLRLSCAASGFTPDDYAMGWFRQAPGKEREFVAAINSG GSYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDRGPWGQGT LVTVSS 6-85 2036 EVQLVESGGGLVQPGGSLRLSCAASGGTFSVFAMGWFRQAPGKEREFVSAINWS GGSLLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCALFGDFDYWGQ GTLVTVSS 6-86 2037 EVQLVESGGGLVQPGGSLRLSCAASGPISGINRMGWFRQAPGKEREFVAVITSNG RPSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCVRLSSGYFDFDYWG QGTLVTVSS 6-87 2038 EVQLVESGGGLVQPGGSLRLSCAASGTSIMVGAMGWFRQAPGKEREFVAIIRGD GRTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARFAGWDAFDIW GQGTLVTVSS 6-88 2039 EVQLVESGGGLVQPGGSLRLSCAASGRTFSTHWMGWFRQAPGKEREFVAVINWS GGSIYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARLSSDGYNYFD FWGQGTLVTVSS 6-89 2040 EVQLVESGGGLVQPGGSLRLSCAASGTIFASAMGWFRQAPGKEHQFVAWNWN GSSTVYADNVKGRFTIIADNSKNTAYLQMNSLKPEDTAVYYCTTVDQYFNYWG QGTLVTVSS 6-90 2041 EVQLVESGGGLVQPGGSLRLSCAASGFPFSIWPMGWFRQAPGKEREFVAAVRWS STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATGECDGGSCSLAY WGQGTLVTVSS 6-91 2042 EVQLVESGGGLVQPGGSLRLSCAASGRTFGNYAMGWFRQAPGKEREFVASISSS GVSKHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCVRFGSSWARDL DQWGQGTLVTVSS 6-92 2043 EVQLVESGGGLVQPGGSLRLSCAASGFLFDSYASMGWFRQAPGKEREFVATIWR RGNTYYANYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTETGTAAW GQGTLVTVSS 6-93 2044 EVQLVESGGGLVQPGGSLRLSCAASGLPFSTKSMGWFRQAPGKEREFVAAISMSG LTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCLKVLGGDYEADNW FDYWGQGTLVTVSS 6-94 2045 EVQLVESGGGLVQPGGSLRLSCAASGNIFRIETMGWFRQAPGKEREFVAGIIRSGG ETLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARSLYYDRSGSYYF DYWGQGTLVTVSS 6-95 2046 EVQLVESGGGLVQPGGSLRLSCAASGIPSSIRAMGWFRQAPGKEREFVAVIRWTG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDIGYYDSSGYY NDGGFDYWGQGTLVTVSS 6-96 2047 EVQLVESGGGLVQPGGSLRLSCAASGFTLSGNWMGWFRQAPGKEREFVAIITSG GRTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAGHATFGGSSSSY YYGMDVWGQGTLVTVSS 6-97 2048 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSLAMGWFRQAPGKEREFVAAITWS GDITNYADSVKGRFTITADNSKNTAYLQMNSLKPEDTAVYYCLRLSSSGFDHWG QGTLVTVSS 6-98 2049 EVQLVESGGGLVQPGGSLRLSCAASGTFGHYAMGWFRQAPGKEREFVAAINWSS RSTVYADSVKGRFTITADNSKNTAYLQMNSLKPEDTAVYYCAKSDGLMGELRSA SAFDIWGQGTLVTVSS 6-99 2050 EVQLVESGGGLVQPGGSLRLSCAASGIPFRSRTMGWFRQAPGKEREFVAGISRSG ASTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTHANDYGDYWGQ GTLVTVSS 6-100 2051 EVQLVESGGGLVQPGGSLRLSCAASGGTFSTSWMGWFRQAPGKEREYVAHITAG GLSNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARLLVREDWYFDL WGQGTLVTVSS 6-101 2052 EVQLVESGGGLVQPGGSLRLSCAASGGTFSLFAMGWFRQAPGKEREFVAAISWT GDSTYYKYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAYNNSSGE YWGQGTLVTVSS 6-102 2053 EVQLVESGGGLVQPGGSLRLSCAASGSSFSAYAMGWFRQAPGKEREFVSAIDSEG TTTYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAGDYNFWSGFDHW GQGTLVTVSS 6-103 2054 EVQLVESGGGLVQPGGSLRLSCAASGRTSSPIAMGWFRQAPGKEREPVAVRWSD DYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKKLGGYYAFDI WGQGTLVTVSS 6-104 2055 EVQLVESGGGLVQPGGSLRLSCAASGLTFNQYTMGWFRQAPGKEREFVASITDG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDSRYMDVWGQ GTLVTVSS 6-105 2056 EVQLVESGGGLVQPGGSLRLSCAASGPTFSSMGWFRQAPGKEREFVAAISWDGG ATAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAIEIVVGGIYWGQG TLVTVSS 6-106 2057 EVQLVESGGGLVQPGGSLRLSCAASGIPSTLRAMGWFRQAPGKEREFVAATSWS GGSKYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDLYYMDVW GQGTLVTVSS 6-107 2058 EVQLVESGGGLVQPGGSLRLSCAASGGVGFSVTNMGWFRQAPGKEREFVAVISS SSSTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTTFNWNDEGFDY WGQGTLVTVSS 6-108 2059 EVQLVESGGGLVQPGGSLRLSCAASGGTFGSYGMGWFRQAPGKEREFVAAIRWS GGITYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARERYWNPLPYY YYGMDVWGQGTLVTVSS 6-109 2060 EVQLVESGGGLVQPGGSLRLSCAASGGTFSTYAMGWFRQVPGKEREFVASIDWS GLTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGPFYMYCSGTK CYSTNWFDPWGQGTLVTVSS 6-110 2061 EVQLVESGGGLVQPGGSLRLSCAASGPIYAVNRMGWFRQAPGKEREFVAGIWRS GGHRDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGEIDILTGYW YDYWGQGTLVTVSS 6-111 2062 EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMGWFRQAPGKEREFVGGISRS GVSTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTTLLYYYDSSGY SFDAFDIWGQGTLVTVSS 6-112 2063 EVQLVESGGGLVQPGGSLRLSCAASGGTFSAYHMGWFRQAPGKERELVTIIDNG GPTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTALLYYFDNSGYN FDPFDIWGQGTLVTGSS

TABLE 36 Reformatted SARS-CoV-2 S1 Variant Sequences SEQ ID Name NO Amino Acid Sequence 2-H1 2064 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYATDWVRQAPGKGLEWVSIISGSG GATYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGGYCSSDTCW WEYWLDPWGQGTLVTVSS 2-H2 2065 EVQLLESGGGLVQPGGSLRLSCAASGFTFSAFAMGWVRQAPGKGLEWVSAITASG DITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQSDGLPSPWHFD LGGQGTLVTVSS 2-H3 2066 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAISGSG DITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPWHFD LWGQGTLVTVSS 2-H4 2067 EVQLLESGGGLVQPGGSLRLSCAASGFTFSRHAMNWVRQAPGKGLEWVSGISGSG DETYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPASYYDSSGY YWHNGMDVWGQGTLVTVSS 2-H5 2068 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAISGSG DITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADCLPSPWYLD LWGQGTLVTVSS 2-H6 2069 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAISGSG DITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPWHFD LWGQGTLVTVSS 2-H7 2070 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYPMNWVRQAPGKGLEWVSTISGSG GNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRHDEYSFDYWGQ GTLVTVSS 2-H8 2071 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAITGSG DITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPWHFD LWGQGTLVTVSS 2-H9 2072 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYPMNWVRQAPGKGLEWVSTISGSG GITFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRHDEYSFDYWGQ GTLVTVSS 2-H10 2073 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYPMNWVRQAPGKGLEWVSAISGSG DNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRHDEYSFDYWGQ GTLVTVSS 2-H11 2074 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAITGTG DITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPWGQ GTLVTVSS 2-H12 2075 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYPMNWVRQAPGKGLEWVSAITGSG DITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRHDEYSFDYWGQ GTLVTVSS 2-H13 2076 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAISGSG DITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPWHFD LWGQGTLVTVSS 2-H14 2077 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDFAMAWVRQAPGKGLEWVSAISGSG DITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREADGLHSPWHFD LWGQGTLVTVSS 2-H15 2078 EVQLLESGGGLVQPGGSLRLSCAASGFTFPRYAMSWVRQAPGKGLEWVSTISGSG STTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLIDAFDIWGQGT LVTVSS 2-L1 2079 DIQMTQSPSSLSASVGDRVTITCRASQSIHRFLNWYQQKPGKAPKLLIYAASNLHS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYGLPPTFGQGTKVEIK 2-L2 2080 DIQMTQSPSSLSASVGDRVTITCRASQSIHISLNWYQQKPGKAPKLLIYLASPLASG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-L3 2081 DIQMTQSPSSLSASVGDRVTITCRASQSIHTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-L4 2082 DIQMTQSPSSLSASVGDRVTITCRASQTINTYLNWYQQKPGKAPKLLIYSASTLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTFTFGQGTKVEIK 2-L5 2083 DIQMTQSPSSLSASVGDRVTITCRASQNIHTYLNWYQQKPGKAPKLLIYAASTFAK GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-L6 2084 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-L7 2085 DIQMTQSPSSLSASVGDRVTITCRASQSIGNYLNWYQQKPGKAPKLLIYGVSSLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSAPLTFGQGTKVEIK 2-L8 2086 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-L9 2087 DIQMTQSPSSLSASVGDRVTITCRASQSIDNYLNWYQQKPGKAPKLLIYGVSALQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSAPPYFFGQGTKVEIK 2-L10 2088 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYGASALES GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSAPPYFFGQGTKVEIK 2-L11 2089 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-L12 2090 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYGVSALQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYFFGQGTKVEIK 2-L13 2091 DIQMTQSPSSLSASVGDRVTITCRASQSIDTYLNWYQQKPGKAPKLLIYAASALAS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSAPPYTFGQGTKVEIK 2-L14 2092 DIQMTQSPSSLSASVGDRVTITCRASQSIDNYLNWYQQKPGKAPKLLIYGVSALQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSAPLTFGQGTKVEIK 2-L15 2093 DIQMTQSPSSLSASVGDRVTITCRASQRIGTYLNWYQQKPGKAPKLLIYAASNLEG GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYSTTWTFGQGTKVEIK 2-H16 2094 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSVISGSG GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGYRDYLWYFD LWGQGTLVTVSS 2-H17 2095 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSAISGSA GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVRQGLRRTWYY FDYWGQGTLVTVSS 2-H18 2096 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMYWVRQAPGKGLEWVSAISGSA GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDTNDFWSGYSIF DPWGQGTLVTVSS 2-H19 2097 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVSVISGSG GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGYRDYLWYFD LWGQGTLVTVSS 2-H20 2098 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSVISGSG GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGPLVGWYFDLW GQGTLVTVSS 2-L16 2099 DIQMTQSPSSLSASVGDRVTITCTGTSSDVGSYDLVSWYQQKPGKAPKLLIYEGNK RPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSSVVFGQGTKVEIK 2-L17 2100 DIQMTQSPSSLSASVGDRVTITCTGTSSDVGSSNLVSWYQQKPGKAPKLLIYEGSK RPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSLYVFGQGTKVEIK 2-L18 2101 DIQMTQSPSSLSASVGDRVTITCTGTSSDIGSYNLVSWYQQKPGKAPKLLIYEGTKR PSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSRTYVFGQGTKVEIK 2-L19 2102 DIQMTQSPSSLSASVGDRVTITCTGTSTDVGSYNLVSWYQQKPGKAPKLLIYEGTK RPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSYTSVVFGQGTKVEIK 2-L20 2103 DIQMTQSPSSLSASVGDRVTITCSSNVGSYNLVSWYQQKPGKAPKLLIYEGTK RPSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCCSYAGSSSFVVFGQGTKVEIK

TABLE 37 Reformatted ACE2 Variant Sequences SEQ ID Name NO Amino Acid Sequence 3-H1 2104 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSHAMSWVRQAPGKGLEWVSSISGGG ASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVKYLTTSSGWPR PYFDNWGQGTLVTVSS 3-H2 2105 EVQLLESGGGLVQPGGSLRLSCAASGFTFSAYSMSWVRQAPGKGLEWVSAISGSG GSRYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGRSKWPQANGAFDI WGQGTLVTVSS 3-H3 2106 EVQLLESGGGLVQPGGSLRLSCAASGFMFGNYAMSWVRQAPGKGLEWVAAISGS GGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRGYSSSWYG GFDYWGQGTLVTVSS 3-H4 2107 EVQLLESGGGLVQPGGSLRLSCAASGFTFRNHAMAWVRQAPGKGLEWVSGISGSG GTTYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGTRFLQWSLPLD VWGQGTLVTVSS 3-H5 2108 EVQLLESGGGLVQPGGSLRLSCAASGFTIPNYAMSWVRQAPGKGLEWVSGISGAG ASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHTWWKGAGFFD HWGQGTLVTVSS 3-H6 2109 EVQLLESGGGLVQPGGSLRLSCAASGFTFRNYAMAWVRQAPGKGLEWVSGISGSG GTTYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGTRFLEWSLPLD VWGQGTLVTVSS 3-H7 2110 EVQLLESGGGLVQPGGSLRLSCAASGFTIRNYAMSWVRQAPGKGLEWVSSISGGG ASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVKYLTTSSGWPR PYFDNWGQGTLVTVSS 3-H8 2111 EVQLLESGGGLVQPGGSLRLSCAASGFTIPNYAMSWVRQAPGKGLEWVSGISGSG ASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHTWWKGAGFFD HWGQGTLVTVSS 3-H9 2112 EVQLLESGGGLVQPGGSLRLSCAASGFTITNYAMSWVRQAPGKGLEWVSGISGSG AGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHAWWKGAGFF DHWGQGTLVTVSS 3-H10 2113 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSHAMSWVRQAPGKGLEWVSSISGGG ASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVKYLTTSSGWPR PYFDNWGQGTLVTVSS 3-H11 2114 EVQLLESGGGLVQPGGSLRLSCAASGFTITNYAMSWVRQAPGKGLEWVSGISGSG ASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHTWWKGAGFFD HWGQGTLVTVSS 3-H12 2115 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSHAMNWVRQAPGKGLEWVSAISGSG GSTNYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGLKFLEWLPSAF DIWGQGTLVTVSS 3-H13 2116 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSHAMSWVRQAPGKGLEWVSSISGGG ASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVKYLTTSSGWPR PYFDNWGQGTLVTVSS 3-H14 2117 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSYAMSWVRQAPGKGLEWVSSISGGG ASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVKYLTTSSGWPR PYFDNWGQGTLVTVSS 3-H15 2118 EVQLLESGGGLVQPGGSLRLSCAASGFTITNYAMSWVRQAPGKGLEWVSGISGSG AGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHTWWKGAGFFD HWGQGTLVTVSS 3-L1 2119 DIQMTQSPSSLSASVGDRVTITCRASQSIRKYLNWYQQKPGKAPKLLIYASSTLQRG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLSTPFTFGQGTKVEIK 3-L2 2120 DIQMTQSPSSLSASVGDRVTITCRASQNIKTYLNWYQQKPGKAPKLLIYAASKLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTSPTFGQGTKVEIK 3-L3 2121 DIQMTQSPSSLSASVGDRVTITCRASQTIYSYLNWYQQKPGKAPKLLIYATSTLQGG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHRGTFGQGTKVEIK 3-L4 2122 DIQMTQSPSSLSASVGDRVTITCRASRSIRRYLNWYQQKPGKAPKLLIYASSSLQAG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTLLTFGQGTKVEIK 3-L5 2123 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASSSLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSPPFTFGQGTKVEIK 3-L6 2124 DIQMTQSPSSLSASVGDRVTITCRASRSISRYLNWYQQKPGKAPKLLIYAASSLQAG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSSLLTFGQGTKVEIK 3-L7 2125 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASSTLQRG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLSPPFTFGQGTKVEIK 3-L8 2126 DIQMTQSPSSLSASVGDRVTITCRASQSIGRYLNWYQQKPGKAPKLLIYASSSLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSLPRTFGQGTKVEIK 3-L9 2127 DIQMTQSPSSLSASVGDRVTITCRASQSIGRYLNWYQQKPGKAPKLLIYAASSLKSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSLPRTFGQGTKVEIK 3-L10 2128 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASSTLQRG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLSTPFTFGQGTKVEIK 3-L11 2129 DIQMTQSPSSLSASVGDRVTITCRASQSIGRYLNWYQQKPGKAPKLLIYAASSLKSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSLPLTFGQGTKVEIK 3-L12 2130 DIQMTQSPSSLSASVGDRVTITCRTSQSINTYLNWYQQKPGKAPKLLIYGASNVQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYRIPRTFGQGTKVEIK 3-L13 2131 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASSTLQRG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSFSPPFTFGQGTKVEIK 3-L14 2132 DIQMTQSPSSLSASVGDRVTITCRASQSIGKYLNWYQQKPGKAPKLLIYASSTLQRG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSFSTPFTFGQGTKVEIK 3-L15 2133 DIQMTQSPSSLSASVGDRVTITCRASQSIGRYLNWYQQKPGKAPKLLIYAASSLKSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSLPRTFGQGTKVEIK 3-H16 2134 EVQLLESGGGLVQPGGSLRLSCAASGFTFTNFAMSWVRQAPGKGLEWVSAISGRG GGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARD AHGYYYDSSG YDDWGQGTLVTVSS 3-H17 2135 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSYPMSWVRQAPGKGLEWVSTISGSG GITYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGVYGSTVTTCH WGQGTLVTVSS 3-H18 2136 EVQLLESGGGLVQPGGSLRLSCAASGFTLTSYAMSWVRQAPGKGLEWVSAISGSG VDTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARPTNWGFDYWGQ GTLVTVSS 3-H19 2137 EVQLLESGGGLVQPGGSLRLSCAASGFTFINYAMSWVRQAPGKGLEWVSTISTSGG NTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARADSNWASSAYWG QGTLVTVSS 3-H20 2138 EVQLLESGGGLVQPGGSLRLSCAASGFPFSTYAMSWVRQAPGKGLEWVSGISVSG GFTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPYSYGYYYYY GMDVWGQGTLVTVSS 3-H21 2139 EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSGISGGG VSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARARNWGPSDYWG QGTLVTVSS 3-H22 2140 EVQLLESGGGLVQPGGSLRLSCAASGFIFSDYAMTWVRQAPGKGLEWVSAISGSA FYADSVKGRFTISRDNSKNTLYLQMNSLRAED TAVYYCARDATYSSSWYNWFDP WGQGTLVTVSS 3-H23 2141 EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMTWVRQAPGKGLEWVSDISGSG GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGTVTSFDFWGQ GTLVTVSS 3-H24 2142 EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYAMGWVRQAPGKGLEWVSFISGSG GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDYHSASWFSAA ADYWGQGTLVTVSS 3-H25 2143 EVQLLESGGGLVQPGGSLRLSCAASGFTFASYAMTWVRQAPGKGLEWVSAISESG GSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGQEYSSGSSYF DYWGQGTLVTVSS 3-H26 2144 EVQLLESGGGLVQPGGSLRLSCAASGFTFSEYAMSWVRQAPGKGLEWVSAITGSG GSTYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSQTPYCGGDCP ETFDYWGQGTLVTVSS 3-H27 2145 EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYAMSWVRQAPGKGLEWVSGISGG GTSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLYSSGWYGF DYWGQGTLVTVSS 3-H28 2146 EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYAMNWVRQAPGKGLEWVSAISGS VGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDNYDFWSGYY TNWFDPWGQGTLVTVSS 3-H29 2147 EVQLLESGGGLVQPGGSLRLSCAASGFTFTNHAMSWVRQAPGKGLEWVSAISGSG SNIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSLSVTMGRGVV TYYYYGMDFWGQGTLVTVSS 3-L16 2148 DIQMTQSPSSLSASVGDRVTITCRASQIIGSYLNWYQQKPGKAPKLLIYTTSNLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYITPWTFGQGTKVEIK 3-L17 2149 DIQMTQSPSSLSASVGDRVTITCRASQSISRYINWYQQKPGKAPKLLIYEASSLESGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHITPLTFGQGTKVEIK 3-L18 2150 DIQMTQSPSSLSASVGDRVTITCRASQSIYTYLNWYQQKPGKAPKLLIYSASNLHSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSDTTPWTFGQGTKVEIK 3-L19 2151 DIQMTQSPSSLSASVGDRVTITCRASQSIATYLNWYQQKPGKAPKLLIYGASSLEGG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTFSSPFTFGQGTKVEIK 3-L20 2152 DIQMTQSPSSLSASVGDRVTITCRASQNINTYLNWYQQKPGKAPKWYSASSLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSSLTPWTFGQGTKVEIK 3-L21 2153 DIQMTQSPSSLSASVGDRVTITCRASQGIATYLNWYQQKPGKAPKLLIYYASNLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTRFTFGQGTKVEIK 3-L22 2154 DIQMTQSPSSLSASVGDRVTITCRASERISNYLNWYQQKPGKAPKLLIYTASNLESG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTPPRTFGQGTKVEIK 3-L23 2155 DIQMTQSPSSLSASVGDRVTITCRASQSISSSLNWYQQKPGKAPKLLIYAASRLQDG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPRSFGQGTKVEIK 3-L24 2156 DIQMTQSPSSLSASVGDRVTITCRASQSISSHLNWYQQKPGKAPKLLIYRASTLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTYNTPQTFGQGTKVEIK 3-L25 2157 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLIWYQQKPGKAPKLLIYAASRLHSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQGYNTPRTFGQGTKVEIK 3-L26 2158 DIQMTQSPSSLSASVGDRVTITCRASPSISTYLNWYQQKPGKAPKLLIYTASRLQTG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTYSTPSSFGQGTKVEIK 3-L27 2159 DIQMTQSPSSLSASVGDRVTITCRASQNIAKYLNWYQQKPGKAPKLLIYGASGLQS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSHSPPITFGQGTKVEIK 3-L28 2160 DIQMTQSPSSLSASVGDRVTITCRASQSIGTYLNWYQQKPGKAPKLLIYAASNLHS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQESYSAPYTFGQGTKVEIK 3-L29 2161 DIQMTQSPSSLSASVGDRVTITCRASQSISPYLNWYQQKPGKAPKLLIYKASSLQSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSSSTPYTFGQGTKVEIK

TABLE 38 Reformatted ACE2 Variant Sequences SEQ ID Name NO Amino Acid Sequence 4-51 2162 EVQLVESGGGLVQPGGSLRLSCAASGPGTAIMGWFRQAPGKEREFVARISTSGGST KYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARTTVTTPPLIWGQGTL VTVSS 4-52 2163 EVQLVESGGGLVQPGGSLRLSCAASGRSFSNSVMGWFRQAPGKEREFVARITWNG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQG TLVTVSS 4-53 2164 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAVSWS GSGVYYADSVKGRFTITADNSKNTAYLQMNSLKPENTAVYYCATDPPLFWGQGT LVTVSS 4-54 2165 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDARMGWFRQAPGKEREFVGAVSWS GGTTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTEDPYPRWGQ GTLVTVSS 4-49 2166 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSA GYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARASPNTGWHFDH WGQGTLVTVSS 4-55 2167 EVQLVESGGGLVQPGGSLRLSCAASGSGLSINAMGWFRQAPGKERESVAAISWSG GSTYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAYQAGWGDW GQGTLVTVSS 4-39 2168 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNAAMGWFRQAPGKEREFVARILWT GASRNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQ GTLVTVSS 4-56 2169 EVQLVESGGGLVQPGGSLRLSCAASGFSLDYYGMGWFRQAPGKERESVAAISWN GDFTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKRANPTGAYFD YWGQGTLVTVSS 4-33 2170 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRHDMGWFRQAPGKEREFVAGINWES GSTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRGVYGGRWY RTSQYTWGQGTLVTVSS 4-57 2171 EVQLVESGGGLVQPGGSLRLSCAASGLTFRNYAMGWFRQAPGKEREFVAAIGSG GYTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVKPGWVARDPSQ YNWGQGTLVTVSS 4-25 2172 EVQLVESGGGLVQPGGSLRLSCAASGGTFSRYAMGWFRQAPGKEREWVSAVDSG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAASPSLRSAWQWG QGTLVTVSS 4-58 2173 EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYDMGWFRQAPGKEREFVAAVTWS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRA ADYDWGQGTLVTVSS 4-59 2174 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSA GYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPLFCWHFDL WGQGTLVTVSS 4-6 2175 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDIMGWFRQAPGKEREFVAAIHWSA GYTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGHVDL WGQGTLVTVSS 4-61 2176 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSA DYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPNTGWHFDH WGQGTLVTVSS 4-3 2177 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSA GYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATATPNTGWHFDH WGQGTLVTVSS 4-62 2178 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWS GGSTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-43 2179 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAGINWS GGNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-5 2180 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWT GGYTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-42 2181 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKERECVAAINWS GGNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-63 2182 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDYTMGWFRQAPGKEREFVAAINWS GGYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-6 2183 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYGMGWFRQAPGKEREFVATINWS GALTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATLPFYDFWSGY YTGYYYMDVWGQGTLVTVSS 4-40 2184 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFLAGVTWS GSSTFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-21 2185 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDIMGWFRQAPGKEREFVAAISWSG GNTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-64 2186 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSA GYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATASPNTGWHFDH WGQGTLVTVSS 4-47 2187 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDDYVMGWFRQAPGKEREFVAAVSG SGDDTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTR AADYDWGQGTLVTVSS 4-65 2188 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSA GYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATEPPLSCWHFDL WGQGTLVTVSS 4-18 2189 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSG GYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPNTGWHFDH WGQGTLVTVSS 4-66 2190 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREIVAAINWS AGYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCCHFDL WGQGTLVTVSS 4-36 2191 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAISWSG GTTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-67 2192 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWS GDSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-16 2193 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWS GGTTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-11 2194 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAIHWS GSSTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-68 2195 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKERELVGTINWS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-34 2196 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSG GYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-28 2197 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKERELVAAINWN GGNTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-69 2198 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAINWS GGTTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-7 2199 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSA GYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGHVDL WGQGTLVTVSS 4-71 2200 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREWVASINWS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-23 2201 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAGISWN GGSIYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-9 2202 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYEMGWFRQAPGKEREFVAAISWR GGTTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRA GDYDWGQGTLVTVSS 4-72 2203 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWS GGYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGHVD LWGQGTLVTVSS 4-73 2204 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAINWS GGSTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-29 2205 EVQLVESGGGLVQPGGSLRLSCAASGVTLDDYAMGWFRQAPGKEREFVAVINWS GGSTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGGGWVPSSTS ESLNWYFDRWGQGTLVTVSS 4-41 2206 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSG GTTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCCHVDLW GQGTLVTVSS 4-74 2207 EVQLVESGGGLVQPGGSLRLSCAASGLTFSDDTMGWFRQAPGKEREFVAAVSWS GGNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-75 2208 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWT GGYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-31 2209 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVATINWTA GYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCWHFDH WGQGTLVTVSS 4-32 2210 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWS GGNTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-15 2211 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYTMGWFRQAPGKEREFVAAINWS GGNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-14 2212 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAGINWS GNGVYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-76 2213 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYAMGWFRQAPGKERELVAPINWS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-50 2214 EVQLVESGGGLVQPGGSLRLSCAASGGTFSNSGMGWFRQAPGKERELVAVVNWS GRRTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVPWMDYNRRD WGQGTLVTVSS 4-17 2215 EVQLVESGGGLVQPGGSLRLSCAASGQLANFASYAMGWFRQAPGKEREFVAAIT RSGSSTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTMNPNPRW GQGTLVTVSS 4-37 2216 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDIMGWFRQAPGKEREFVAAINWTG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-44 2217 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSA GYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATARPNTGWHFDH WGQGTLVTVSS 4-77 2218 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREWVGSINWS GGSTYYADSVKGRFTISADNS KNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-78 2219 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAGMTWS GSSTFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-79 2220 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERECVAAINWS GDYTDYADSVKGRFTISADNSKNTAYLQMNSLKPED TAVYYCATDPPLFWGQGT LVTVSS 4-8 2221 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVGGINWSG GYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-81 2222 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAVNWS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-82 2223 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYAMGWFRQAPGKEREFVAAINWS GGYTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-83 2224 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWS GGYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-35 2225 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSA GYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARASPNTGWHFDR WGQGTLVTVSS 4-45 2226 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSG GYTHYADSVKGRFTISADNS KNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-84 2227 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAITWSG GRTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDRPLFWGQGTL VTVSS 4-85 2228 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSG GYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATASPNTGWHFDH WGQGTLVTVSS 4-86 2229 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAIHWS GSSTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-87 2230 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDYTMGWFRQAPGKEREWVAAINWS GGTTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-88 2231 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWS GDNTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-89 2232 EVQLVESGGGLVQPGGSLRLSCAASGFAFGDNWIGWFRQAPGKEREWVASISSGG TTAYADNVKGRFTIIADNSKNTAYLQMNSLKPEDTAVYYCAHRGGWLRPWGYW GQGTLVTVSS 4-9 2233 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVGRINWS GGNTYYADSVKGRFTISADNSKNTAYLQMNSLKPED TAVYYCATDPPLFWGQGT LVTVSS 4-91 2234 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVGGISWSG GNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-92 2235 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-46 2236 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWS GGYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT VLVTVSS 4-20 2237 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSA DYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCWHFDH VWGQGTLVTVSS 4-93 2238 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAINWS GSSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-4 2239 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREMVAAINWI AGYTADADSVRRLFTITADNNKNTAHLMMNLLKPENTAVYYCAEPSPNTGWHFD VHWGQGTLVTVSS 4-2 2240 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDDTMGWFRQAPGKEREFVAAINWS GGNTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-94 2241 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDTMGWFRQAPGKEREFVAAINWS GDNTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-95 2242 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSA GYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPLFCWHFDH WGQGTLVTVSS 4-12 2243 EVQLVESGGGLVQPGGSLRLSCAASGFTFGDYVMGWFRQAPGKEREIVAAINWN AGYTAYADSVRGLFTITADNSKNTAYLQMNSLKPEDTAVYYCAKASPNTGWHFD HWGQGTLVTVSS 4-30 2244 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYTMGWFRQAPGKEREFVAAINWT GGYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT LVTVSS 4-27 2245 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSA GYTAYADSVKGLFTITADNSKNTAYLQMNILKPEDTAVYYCARATPNTGWHFDH WGQGTLVTVSS 4-22 2246 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREFVAAINWSG DNTHYADSVKGRFTISADNS KNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGTL VTVSS 4-96 2247 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKEREIVAAINWSA GYTPYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFCCHFDH WGQGTLVTVSS 4-97 2248 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWSA GYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATAPPNTGWHFDH WGQGTLVTVSS 4-98 2249 EVQLVESGGGLVQPGGSLRLSCAASGFTWGDYTMGWFRQAPGKEREFVAAINWS GGNTYYADSVKGRFTISADNSKNTAYLQMNSLKPED TAVYYCAADRRGLASTRA ADYDWGQGTLVTVSS 4-99 2250 EVQLVESGGGLVQPGGSLRLSCAASGIPSTLRAMGWFRQAPGKEREFVAAVSSLG PFTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKPGWVARDPSQ YNWGQGTLVTVSS 4-100 2251 EVQLVESGGGLVQPGGSLRLSCAASGFSFDDDYVMGWFRQAPGKEREFVAAINW SGGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPED TAVYYCAAD RRGLASTR AADYDWGQGTLVTVSS 4-101 2252 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNAAMGWFRQAPGKEREFVARILWT GASRSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQ GTLVTVSS 4-102 2253 EVQLVESGGGLVQPGGSLRLSCAASGGTFGVYHMGWFRQAPGKEREGVAAINMS GDDSAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAILVGPGQVEFDH WGQGTLVTVSS 4-103 2254 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMGWFRQAPGKEREFVARI-- SGSTFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAALPFVCPSGSYS DYGDEYDWGQGTLVTVSS 4-104 2255 EVQLVESGGGLVQPGGSLRLSCAASGRTFSGDFMGWFRQAPGKEREFVGRINWSG GNTYYADSVRGLFTITADNNKNTAYLMMNLLKPEDTAVYYCPTDPPLFWGLGTL VTWSS 4-105 2256 EVQLVESGGGLVQPGGSLRLSCAASGSTLRDYAMGWFRQAPGKERESVAAITWS GGSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASLLAGDRYFDY WGQGTLVTVSS 4-106 2257 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYTMGWFRQAPGKEREFVAAITDNG GSKYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAA DYDWGQGTLVTVSS 4-107 2258 EVQLVESGGGLVQPGGSLRLSCAASGGTFSSYGMGWFRQAPGKEREFVAAINWS GASTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDWRDRTWGN SLDYWGQGTLVTVSS 4-108 2259 EVQLVESGGGLVQPGGSLRLSCAASGFSFDDDYVMGWFRQAPGKEREFVAAISW SEDNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTR AADYDWGQGTLVTVSS 4-109 2260 EVQLVESGGGLVQPGGSLRLSCAASGFSFDDDYVMGWFRQAPGKEREFVAAVSG SGDDTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTR AADYDWGQGTLVTVSS 4-11 2261 EVQLVESGGGLVQPGGSLRLSCAASGNIAAINVMGWFRQAPGKEREFVAAISASG RRTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARRVYYYDSSGPP GVTFDIWGQGTLVTVSS 4-111 2262 EVQLVESGGGLVQPGGSLRLSCAASGIITSRYVMGWFRQAPGKEREGVAAISTGGS TIYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARQDSSSPYFDYWGQG TLVTVSS 4-112 2263 EVQLVESGGGLVQPGGSLRLSCAASGFSFDDDYVMGWFRQAPGKEREFVAAISNS GLSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRA ADYDWGQGTLVTVSS 4-113 2264 EVQLVESGGGLVQPGGSLRLSCAASGSISSINVMGWFRQAPGKEREFVATMRWST GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAQRVRGFFGPLRTT PSWYEWGQGTLVTVSS 4-114 2265 EVQLVESGGGLVQPGGSLRLSCAASGLTFILYRMGWFRQAPGKEREFVAAINNFG TTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARTHYDFWSGYTSR TPNYFDYWGQGTLVTVSS 4-115 2266 EVQLVESGGGLVQPGGSLRLSCAASGGTFSVYHMGWFRQAPGKEREPVAAISWS GGSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAVNTWTSPSFDS WGQGTLVTVSS 4-116 2267 EVQLVESGGGLVQPGGSLRLSCAASGRAFSTYGMGWFRQAPGKEREFVAGINWS GDTPYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAREVGPPPGYFDL WGQGTLVTVSS 4-117 2268 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDIAMGWFRQAPGKEREFVASINWGG GNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKGIWDYLGRRD FGDWGQGTLVTVSS 4-118 2269 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSARMGWFRQAPGKEREFVAAISWSG DNTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQG TLVTVSS 4-119 2270 EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYAMGWFRQAPGKEREWVATINGD DYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCVATPGGYGLWGQ GTLVTVSS 4-12 2271 EVQLVESGGGLVQPGGSLRLSCAASGITFRRHDMGWFRQAPGKEREFVAAIRWSS SSTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRGVYGGRWYR TSQYTWGQGTLVTVSS 4-121 2272 EVQLVESGGGLVQPGGSLRLSCAASGTAASFNPMGWFRQAPGKEREFVAAITSGG STNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAIAYEEGVYRWDW GQGTLVTVSS 4-122 2273 EVQLVESGGGLVQPGGSLRLSCAASGNINIINYMGWFRQAPGKEREGVAAIHWNG DSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASGPPYSNYFAYW GQGTLVTVSS 4-123 2274 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYAMGWFRQAPGKERESVAAISGSG GSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKIMGSGRPYFDH WGQGTLVTVSS 4-124 2275 EVQLVESGGGLVQPGGSLRLSCAASGNIFTRNVMGWFRQAPGKEREFVAAITSSG STNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARPSSDLQGGVDYW GQGTLVTVSS 4-125 2276 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSIAMGWFRQAPGKEREFVASINWGG GNTIYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKGIWDYLGRRD FGDWGQGTLVTVSS 4-126 2277 EVQLVESGGGLVQPGGSLRLSCAASGIPSTLRAMGWFRQAPGKEREFVAAVSSLG PFTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKPGWVARDPSE YNWGQGTLVTVSS 4-127 2278 EVQLVESGGGLVQPGGSLRLSCAASGFTLDDSAMGWFRQAPGKEREWVAAITNG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARFARGSPYFDFW GQGTLVTVSS 4-128 2279 EVQLVESGGGLVQPGGSLRLSCAASGSISSFNAMGWFRQAPGKERESVAAIDWDG STAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGGGYYGSGSFEY WGQGTLVTVSS 4-129 2280 EVQLVESGGGLVQPGGSLRLSCAASGNIFSDNIIGWFRQAPGKEREMVAYYTSGGS IDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGTAVGRPPPGGMD VWGQGTLVTVSS 4-13 2281 EVQLVESGGGLVQPGGSLRLSCAASGSISSIGAMGWFRQAPGKEREGVAAISSSGS STVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVPPGQAYFDSWG QGTLVTVSS 4-131 2282 EVQLVESGGGLVQPGGSLRLSCAASGFTFDDYGMGWFRQAPGKERELVATITWS GDSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKGGSWYYDSSG YYGRWGQGTLVTVSS 4-132 2283 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYTMGWFRQAPGKEREWVSAISWS TGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRYGPPWYD WGQGTLVTVSS 4-134 2284 EVQLVESGGGLVQPGGSLRLSCAASGGTFSSVGMGWFRQAPGKERELVAVINWS GARTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVPWMDYNRRD WGQGTLVTVSS 4-135 2285 EVQLVESGGGLVQPGGSLRLSCAASGRIFTNTAMGWFRQAPGKEREGVAAINWS GGSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARTSGSYSFDYW GQGTLVTVSS 4-136 2286 EVQLVESGGGLVQPGGSLRLSCAASGEEFSDHWMGWFRQAPGKEREFVGAIHWS GGRTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRA ADYDWGQGTLVTVSS 4-137 2287 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSIAMGWFRQAPGKEREFVAAINWSG ARTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKGIWDYLGRRD FGDWGQGTLVTVSS 4-138 2288 EVQLVESGGGLVQPGGSLRLSCAASGSTSSLRTMGWFRQAPGKEREGVAAISSRD GSTIYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDDSSSPYFDYWG QGTLVTVSS 4-139 2289 EVQLVESGGGLVQPGGSLRLSCAASGGGTFGSYAMGWFRQAPGKEREFVAAISIA SGASGGTTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTMNPNP RWGQGTLVTVSS 4-14 2290 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNAAMGWFRQAPGKEREFVARITWN GGSTFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTENPNPRWGQ GTLVTVSS 4-141 2291 EVQLVESGGGLVQPGGSLRLSCAASGIILSDNAMGWFRQAPGKEREFVAAISWLG ESTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADRRGLASTRAA DYDWGQGTLVTVSS 4-142 2292 EVQLVESGGGLVQPGGSLRLSCAASGRTFGDYIMGWFRQAPGKERESVAAINWN GGYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATTSPNTGWHYY RWGQGTLVTVSS 4-143 2293 EVQLVESGGGLVQPGGSLRLSCAASGFNFNWYPMGWFRQAPGKERESVAAISWT GVSTYTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARWGPGPAGG SPGLVGFDYWGQGTLVTVSS 4-144 2294 EVQLVESGGGLVQPGGSLRLSCAASGSIRSVSVMGWFRQAPGKEREAVAAISWSG VGTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAYQRGWGDWGQ GTLVTVSS 4-145 2295 EVQLVESGGGLVQPGGSLRLSCAASGMTFRLYAMGWFRQAPGKEREFVGAINWL SESTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKPGWVARDPS EYNWGQGTLVTVSS 4-146 2296 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDDAMGWFRQAPGKEREFVAAINWS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATDPPLFWGQGT MVTVSS 4-147 2297 EVQLVESGGGLVQPGGSLRLSCAASGGTFSVYAMGWFRQAPGKEREGVAAISMS GDDAAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKISKDDGGKPR GAFFDSWGQGTLVTVSS 4-148 2298 EVQLVESGGGLVQPGGSLRLSCAASGFALGYYAMGWFRQAPGKERESVAAISSRD GSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARLATGPQAYFHH WGQGTLVTVSS 4-149 2299 EVQLVESGGGLVQPGGSLRLSCAASGFNLDDYAMGWFRQAPGKERESVAAISWD GGATAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVGRGTTAFDS WGQGTLVTVSS 4-15 2300 EVQLVESGGGLVQPGGSLRLSCAASGNTFSGGFMGWFRQAPGKEREFVASIRSGA RTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAQRVRGFFGPLRTTP SWYEWGQGTLVTVSS 4-151 2301 EVQLVESGGGLVQPGGSLRLSCAASGSIRSINIMGWFRQAPGKEREAVAAISWSGG STVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASLLAGDRYFDYWG QGTLVTVSS

TABLE 39 SARS-CoV-2 Variant Variable Heavy Chain Sequences 7-1 2302 EVQLVESGGGLVQPGGSLRLSCAASGFTLGDYVMGWFRQAPGKEREFVAAIHSG GSTYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKEYGGTRRYDRA YNWGQGTLVTVSS 7-2 2303 EVQLVESGGGLVQPGGSLRLSCAASGGGTFGSYAMGWFRQAPGKERELVAAISSG GSTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQG TLVTVSS 7-3 2304 EVQLVESGGGLVQPGGSLRLSCAASGRTYSISAMGWFRQAPGKEREFVAAISMSG DDSAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQLGYESGYSLT YDYDWGQGTLVTVSS 7-4 2305 EVQLVESGGGLVQPGGSLRLSCAASGGTFSTYPMGWFRQAPGKEREFVAAITSDG STLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAATDYNKAYAREGR RYDWGQGTLVTVSS 7-5 2306 EVQLVESGGGLVQPGGSLRLSCAASGSIFRINAMGWFRQAPGKEREFVAAIHWSG SSTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQDRRRGDYYTF DYHWGQGTLVTVSS 7-6 2307 EVQLVESGGGLVQPGGSLRLSCAASGGTFNNYAMGWFRQAPGKERELVAAITSG GSTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQG TLVTVSS 7-7 2308 EVQLVESGGGLVQPGGSLRLSCAASGTIVNINVMGWFRQAPGKEREFVAAIHWSG GLKAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAMNRAGIYEWGQ GTLVTVSS 7-8 2309 EVQLVESGGGLVQPGGSLRLSCAASGSTFSNYAMGWFRQAPGKERELVAAITSGG STSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQGT LVTVSS 7-9 2310 EVQLVESGGGLVQPGGSLRLSCAASGFSFDDYVMGWFRQAPGKEREFVAAISRSG NLKSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKEYGGTRRYDR AYNWGQGTLVTVSS 7-10 2311 EVQLVESGGGLVQPGGSLRLSCAASGSAFRSTVMGWFRQAPGKEREFVAAVIGSS GITDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQG TLVTVSS 7-11 2312 EVQLVESGGGLVQPGGSLRLSCAASGRTFSDAGMGWFRQAPGKEREFVAAISRSG NLKAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVQVNGTWAWGQ GTLVTVSS 7-12 2313 EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAMGWFRQAPGKERELVAAISWN GGSTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQ GTLVTVSS 7-13 2314 EVQLVESGGGLVQPGGSLRLSCAASGGTFSTYVMGWFRQAPGKEREFVAAISWSG ESTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADLMYGVDRRYD WGQGTLVTVSS 7-14 2315 EVQLVESGGGLVQPGGSLRLSCAASGISSSKRNMGWFRQAPGKEREFVAGISWTG GITYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAIAGRGRWGQGTL VTVSS 7-15 2316 EVQLVESGGGLVQPGGSLRLSCAASGRRFSAYGMGWFRQAPGKEREFVAVISRSG TLTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASSGPADARNGER WHWGQGTLVTVSS 7-16 2317 EVQLVESGGGLVQPGGSLRLSCAASGLTFSSFVMGWFRQAPGKEREFVAAISSNG GSTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKEYGGTRRYDR AYNWGQGTLVTVSS 7-17 2318 EVQLVESGGGLVQPGGSLRLSCAASGTVFSISAMGWFRQAPGKEREFVAAISMSG DDTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQLGYESGYSLT YDYDWGQGTLVTVSS 7-18 2319 EVQLVESGGGLVQPGGSLRLSCAASGSIFSPNVMGWFRQAPGKEREFVAAITNGG STKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQRWRGGSYEWG QGTLVTVSS 7-19 2320 EVQLVESGGGLVQPGGSLRLSCAASGIPASIRVMGWFRQAPGKEREFVAAIHWSG SSTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCALSRAIVPGDSEYD YRWGQGTLVTVSS 7-20 2321 EVQLVESGGGLVQPGGSLRLSCAASGRTFSMSAMGWFRQAPGKEREFVSAISWSG GSTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQLGYESGYSLTY DYDWGQGTLVTVSS 7-21 2322 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYAMGWFRQAPGKERELVAAITSGG STDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQGT LVTVSS 7-22 2323 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSYAMGWFRQAPGKERELVAAISTGG STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQGT LVTVSS 7-23 2324 EVQLVESGGGLVQPGGSLRLSCAASGRSFSSVGMGWFRQAPGKEREFVAVISRSG ASTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASAGPADARNGER WAWGQGTLVTVSS 7-24 2325 EVQLVESGGGLVQPGGSLRLSCAASGRAFRRYTMGWFRQAPGKERELIAVINWSG DRRYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAATLAKGGGRWG QGTLVTVSS 7-25 2326 EVQLVESGGGLVQPGGSLRLSCAAMAWAGFARRRAKNAKWWRALPRGGPTYA DSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAGGMWYGSSLYVRFDLLE DGMDWGQGTLVTVSS 7-26 2327 EVQLVESGGGLVQPGGSLRLSCAASGSISSINGMGWFRQAPGKERELVALISRSGG TTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASAGPADARNGERW AWGQGTLVTVSS 7-27 2328 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNNVMGWFRQAPGKERELVAAAISG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQG TLVTVSS 7-28 2329 EVQLVESGGGLVQPGGSLRLSCAASGRTFSISAMGWFRQAPGKEREFVAAISRSGT TMYADSVKGRFTISADNSKNTAYLQMNSLKP EDTAVYYCAAQLGYESGYSLTYD YDWGQGTLVTVSS 7-29 2330 EVQLVESGGGLVQPGGSLRLSCAASGGTFSYYDLAAMGWFRQAPGKEREFVAAIS WSQYNTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARVVVRTA HGFEDNWGQGTLVTVSS 7-30 2331 EVQLVESGGGLVQPGGSLRLSCAASGRTFNNYGMGWFRQAPGKEREFVAVISRSG SLKAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASDPTYGSGRWTW VGQGTLVTVSS 7-31 2332 EVQLVESGGGLVQPGGSLRLNCAASGFTLDDYVMGWFRQTPGKEREFVAAISSSG ALTSYADSVKGRFTISADNS KNTAYLQMNSLKPEDAAVYYCAAKEYGGTRRYDR AYNWGQGTLVTVSS 7-32 2333 EVQLVESGGGLVQPGGSLRLSCAASGRTFNAMGWFRQAPGKEREFVAAIRWSGD MSVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQDRRRGDYYTFD YHWGQGTLVTVSS 7-33 2334 EVQLVESGGGLVQPGGSLRLSCAASGLTFSTYAMGWFRQAPGKEREFVAAITSGG STDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQGT LVTVSS 7-34 2335 EVQLVESGGGLVQPGGSLRLSCAASGSIFTINAMGWFRQAPGKEREGVAAIGSDGS TSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVVRWGADWGQGTL VTVSS 7-35 2336 EVQLVESGGGLVQPGGSLRLSCAASGLTFSSYAMGWFRQAPGKERELVAAITSSS GSTPAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQ GTLVTVSS 7-36 2337 EVQLVESGGGLVQPGGSLRLSCAASGIPFSTRTMGWFRQAPGKEREFVAAISWSQ YNTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARHWGMFSRSEN DYNWGQGTLVTVSS 7-37 2338 EVQLVESGGGLVQPGGSLRLSCAASGRSRFSTYVMGWFRQAPGKEREFVAAISWS QYNTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAGNGGRNYGH SRARYDWGQGTLVTVSS 7-38 2339 EVQLVESGGGLVQPGGSLRLSCAASGLTLSSYGMGWFRQAPGKEREYVAVISRSG SLKAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATRADAEGWWDW GQGTLVTVSS 7-39 2340 EVQLVESGGGLVQPGGSLRLSCAASGSIFRVNVMGWFRQAPGKEREFVAAINNFG TTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAADLPSRWGQGTLV TVSS 7-40 2341 EVQLVESGGGLVQPGGSLRLSCAASGRTFRNYAMGWFRQAPGKERELVAAISSGG STDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQGT LVTVSS 7-41 2342 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSFAMGWFRQAPGKERELVAAISSGG STNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQGT LVTVSS 7-42 2343 EVQLVESGGGLVQPGGSLRLSCAASGTTFRINAMGWFRQAPGKEREFVAAMNWS GGSTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQDRRRGDYYT FDYHWGQGTLVTVSS 7-43 2344 EVQLVESGGGLVQPGGSLRLSCAASGFTLGDYVMGWFRQAPGKEREFVAAIHSG GSTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKEYGGTRRYDR TYNWGQGTLVTVSS 7-44 2345 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRSAMGWFRQAPGKERELVAGILSSG ATVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKAPRDWGQGTLVT VSS 7-45 2346 EVQLVESGGGLVQPGGSLRLSCAASGRTFNNYAMGWFRQAPGKERELVAAITSG GSTDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQG TLVTVSS 7-46 2347 EVQLVESGGGLVQPGGSLRLSCAASGFTFRSYPMGWFRQAPGKEREFVAAINNFG TTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAAKGIGVYGWGQG TLVTVSS 7-47 2348 EVQLVESGGGLVQPGGSLRLSCAASGNIFTRNVMGWFRQAPGKEREFVAAIHWN GDSTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAGSNIGGSRWR YDWGQGTLVTVSS 7-48 2349 EVQLVESGGGLVQPGGSLRLSCAASGRTISRYTMGWFRQAPGKERELVAAIKWSG ASTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKGIWDYLGRRD FGDWGQGTLVTVSS 7-49 2350 EVQLVESGGGLVQPGGSLRLSCAASGFRFSSYGMGWFRQAPGKEREFVAIITSGGL TVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARKTFYFGTSSYPND YAWGQGTLVTVSS 7-50 2351 EVQLVESGGGLVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREGVAAIGSD GSTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVVRWGVDWGQG TLVTVSS 7-51 2352 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSHAMGWFRQAPGKEREFVAGISWSG ESTLTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCADVNGDWGQGT LVTVSS 7-52 2353 EVQLVESGGGLVQPGGSLRLSCAASGMTFRLYAMGWFRQAPGKEREFVAAISWS QYNTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQLGYESGYSL TYDYDWGQGTLVTVSS 7-53 2354 EVQLVESGGGLVQPGGSLRLSCAASGGTFRKLAMGWFRQAPGKEREFVAVISWT GGSSYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARLTSFATWGQG TLVTVSS 7-54 2355 EVQLVESGGGLVQPGGSLRLSCAASGRTFSANGMGWFRQAPGKEREFVAAISASG TLRAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARSPMSPTWDWG QGTLVTVSS 7-55 2356 EVQLVESGGGLVQPGGSLRLSCAASGSAFRSTVMGWFRQAPGKEREFVAAISWTG ESTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATGPYRSYFARSYL WGQGTLVTVSS 7-56 2357 EVQLVESGGGLVQPGGSLRLSCAASGGTFDYSGMGWFRQAPGKEREFVAVVSQS GRTTYYADSVKGLFTITADNSKNTAYLQMNLLKPEDTAVYYCPTATRPGEWDGG QGTLVTVSR 7-57 2358 EVQLVESGGGLVQPGGSLRLSCAASGVFGPIRAMGWFRQAPGKERELVALMGND GSTYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAIGWRWGQGTLVT VSS 7-58 2359 EVQLVESGGGLVQPGGSLRLSCAASGFNFNWYPMGWFRQAPGKEREFVAAIRWS GGITYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATGPYRSYFARSY LWGQGTLVTVSS 7-59 2360 EVQLVESGGGLVQPGGSLRLSCAASGMTFHRYVMGWFRQAPGKERELVASITTG GTPNYADSVKGRFTIITDNNKNTAYLLMINLQPEDTAVYYCCKVPYIWGQGTLGT VGT 7-60 2361 EVQLVESGGGLVQPGGSLRLSCAASGISTMGWFRQAPGKEREFVAAINNFGTTKY ADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAASQSGSGYDWGQGTLV TVSS 7-61 2362 EVQLVESGGGLVQPGGSLRLSCAASGRAFNTRAMGWFRQAPGKERELVALMGN DGSTYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAIGWRWGQGTLV TVSS 7-62 2363 EVQLVESGGGLVQPGGSLRLSCAASGLTDRRYTMGWFRQAPGKEREFVAAINSG GSTLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAGNGGRTYGHSR ARYEWGQGTLVTVSS 7-63 2364 EVQLVESGGGLVQPGGSLRLSCAASGRTFNVMGWFRQAPGKERELVALMGNDGS TYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAVRWGVDWGQGTLV TVSS 7-64 2365 EVQLVESGGGLVQPGGSLRLSCAASGRAFNTRAMGWFRQAPGKERELVALMGN DGSTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAIGWRWGQGTL VTVSS 7-65 2366 EVQVVESGGGVVHPGGSVRMRCAASGVTVDYSGMGWFGQAPGKEREFVAVVSQ SARTTYYADSVKGRFTISADNSKNTEYLQMNSMKPEDTAVYYCATATRPGEWDW GQGTLVTVSS 7-66 2367 EVQLVESGGGLVQPGGSLRLSCAASGRTPRLGAMGWFRQAPGKEREFVAAISRSG GLTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQLVGSNIGGSR WRYDWGQGTLVTVSS 7-67 2368 EVQLVESGGGLVQPGGSLRLSCAASGLTFRNYAMGWFRQAPGKEREFVAAITSGG STLYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGHGT LVTESS 8-1 2369 EVQLVESGGGLVQPGGSLRLSCAASGGRTFSDLAMGWFRQAPGKEREFVALITRS GGTTFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAIGRGSWGQGTL VTVSS 8-2 2370 EVQLVESGGGLVQPGGSLRLSCAASGFTFGEYAMGWFRQAPGKEREFVAAVSSL GPFTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAVLDGYSGSWG QGTLVTVSS 8-3 2371 EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYGMGWFRQAPGKEREFVAAISWSG VRSGVSAIYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTTDLTGDLWY FDLWGQGTLVTVSS 8-4 2372 EVQLVESGGGLVQPGGSLRLSCAASGLTAGTYAMCWFRQAPGKEREGVACASST DGSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAVRTYGSATYD WGQGTLVTVSS 8-5 2373 EVQLVESGGGLVQPGGSLRLSCAASGFTLDDYVMGWFRQAPGKERELVAAVSSL GPFTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKEYGGTRRYD RAYNWGQGTLVTVSS 8-6 2374 EVQLVESGGGLVQPGGSLRLSCAASGPTLGSYVMGWFRQAPGKEREFVAAISWSQ YNTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAQRWRGGSYEW GQGTLVTVSS 8-7 2375 EVQLVESGGGLVQPGGSLRLSCAASGPTFSSYVMGWFRQAPGKEREFVAAISWSQ YNTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAASRSGSGYDWG QGTLVTVSS 8-8 2376 EVQLVESGGGLVQPGGSLRLSCAASGYLYSKDCMGWFRQAPGKEREGVATICTG DGSTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAVIAYEEGVYRW DWGQGTLVTVSS 8-9 2377 EVQLVESGGGLVQPGGSLRLSCAASGFTIDDYAMGWFRQAPGKEREGVAAISGSG DDTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKLPYVSGDYWG QGTLVTVSS 8-10 2378 EVQLVESGGGLVQPGGSLRLSCAASGGRFSDYGMGWFRQAPGKERELVALISRSG NLKSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKTGTSFVWGQG TLVTVSS 8-11 2379 EVQLVESGGGLVQPGGSLRLSCAASGLSFSNYAMGWFRQAPGKERELVAAITSGG STDYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGDWRYGWGQGT LVTVSS 8-12 2380 EVQLVESGGGLVQPGGSLRLSCAASGIPSTLRAMGWFRQAPGKEREFVALINRSG GSQFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAIGRGSWGQGTLV TVSS

TABLE 40 Membrane Protein CDR Sequences SEQ SEQ SEQ ID ID ID Variant NO CDRH1 NO CDRH2 NO CDRH3  9-1 2381 RTFSRLAMG 2453 AAISRSGRSTSY 2525 CAARRSQILFTSRTDYEW A  9-2 2382 SFSIAAMG 2454 ATINYSGGGTYY 2526 CAAVNTFDESAYAAFACYDV A VW  9-3 2383 RTFSRYAMG 2455 AAISRSGKSTYY 2527 CAASSVFSDLRYRKNPKW A  9-4 2384 RTFSKYAMG 2456 ALITPSSRTTYYA 2528 CAIAGRGRW  9-5 2385 RTFRRYAMG 2457 ASINWGGGNTY 2529 CAKTKRTGIFTTARMVDW YA  9-6 2386 RTFSRFAMG 2458 AAIRWSGGRTV 2530 CAIEPGTIRNWRNRVPFARGN YA FGW  9-7 2387 LGIAFSRRTA 2459 AAISWRGGNTY 2531 CAARRWIPPGPIW MG YA  9-8 2388 RTFRRYPMG 2460 AAISRSGGSTYY 2532 CAAKRLRSFASGGSYDW A  9-9 2389 GTLRGYGMG 2461 ASISRSGGSTYY 2533 CAARRRVTLFTSRADYDW A  9-10 2390 RMFSSRSMG 2462 ALINRSGGSQFY 2534 CAARRWIPPGPIW A  9-11 2391 RTFGRRAMG 2463 AGISRGGGTNYA 2535 CAAKGIWDYLGRRDFGDW 10-1 2392 LSSPPFDDFPB 2464 SSIYSDDGDSMY 2536 CARQTFDFWSASLGGNFWYF MG A DLW 10-2 2393 GTFSSYSMG 2465 SAISWIIGSGGTT 2537 CTAGAGDSW NYA 10-3 2394 SIFSTRTMG 2466 ASITKFGSTNYA 2538 CTRGGGRFFDWLYLRW 10-4 2395 RTLWRSNMG 2467 ASISSFGSTKYA 2539 CARGHGRYFDWLLFARPPDY W 10-5 2396 RSLGIYRMG 2468 AAITSGGRKNYA 2540 CAKRTIFGVGRWLDPW 10-6 2397 TTLTFRIMG 2469 PAISSTGLASYT 2541 CSKDRAPNCFACCPNGFDVW 10-7 2398 SRFSGRFNILN 2470 ARIGYSGQSISY 2542 CARGRFLGGTEW MG A 10-8 2399 TLFKINAMG 2471 AQINRHGVTYY 2543 CARGRTIFFGGGRYFDYW A 10-9 2400 IPFRSRTMG 2472 AGITGSGRSQYY 2544 CARGARIFGSVAPWRGGNYY A GMDVW 10-10 2401 FTFSSFRMG 2473 AGISRGGSTNYA 2545 CARASGLWFRRPHVW 10-11 2402 RNFRRNSMG 2474 AGISWSGARTHY 2546 CARVSRRPRSPPGYYYGMDV A W 10-12 2403 RNLRMYRMG 2475 ATIRWSDGSTYY 2547 CTRARLRYFDWLFPTNFDYW A 10-13 2404 GLTFSSNTMG 2476 ASISSSGRTSYA 2548 CARRVRRLWFRSYFDLW 10-14 2405 FTLAYYAMG 2477 AAISWSGRNINY 2549 CARERARWFGKFSVSW A 10-15 2406 RTFSSFPMG 2478 AAISWSGSTSYA 2550 SACGRLGFGAW 10-16 2407 ISSSKRNMG 2479 ATWTSRGITTYA 2551 CARGGPPRLWGSYRRKYFDY W 10-17 2408 RTFSIYAMG 2480 ARTIRGGITKYA 2552 CARGLGWLLGYYW 10-18 2409 RMYNSYSMG 2481 ARISPGGTFYA 2553 CTTSARSGWFWRYFDSW 10-19 2410 RTFRSYGMG 2482 ASISRSGTTMYA 2554 CARRGLLQWFGAPNSWFDP W 10-20 2411 RTIRTMG 2483 ATINSRGITNYA 2555 CTTERDGLLWFRELFRPSW 10-21 2412 RSFSFNAMG 2484 ARISRFGRTNYA 2556 CAKVHSYVWGGHSDYW 10-22 2413 RTYYAMG 2485 GAIDWSGRRITY 2557 CARVRFSRLGGVIGRPIDSW A 10-23 2414 RAFRRYTMG 2486 ASITKFGSTNYA 2558 CAKDRGVLWFGELWYW 10-24 2415 RTFSNYRMG 2487 ASINRGGSTKYA 2559 CASGKGGSATIFHLSRRPLYF DYW 10-25 2416 ITFSPYAMG 2488 ATINWSGGYTV 2560 CAKRKNRGPLWFGGGGWGY YA W 10-26 2417 RTFSGFTMSS 2489 AGIITNGSTNYA 2561 CARRVAYSSFWSGLRKHMD TWMG VW 10-27 2418 RTFRRYSMG 2490 ASITPGGNTNYA 2562 CASRRRWLTPYIFW 10-28 2419 SIFSIGMG 2491 ARIWWRSGATY 2563 CAAISIFGRLKW YA 10-29 2420 RTFTSYRMG 2492 AEISSSGGYTYY 2564 CARVGPLRFLAQRPRLRPDY A W 10-30 2421 RTFSSFRFRA 2493 ALIFSGGSTYYA 2565 CAREWGRWLQRGSYW MG 10-31 2422 RTFGSYGMG 2494 ATISIGGRTYYA 2566 CARGSGSGFMWYHGNNNYD RWRYW 10-32 2423 RTFRSYPMG 2495 ASINRGGSTNYA 2567 CARGRYDFWSGYYRWFDPW 10-33 2424 RTFSRSDMG 2496 AAISWSGGSTSY 2568 CATVPPPRRFLEWLPRRLTYI A W 10-34 2425 RTFRRYTMG 2497 ASMRGSRSYYA 2569 CARMSGFPFLDYW 10-35 2426 SIFRLSTMG 2498 ASISSFGSTYYA 2570 CARTRGIFLWFGESFDYW 10-36 2427 IAFRIRTMG 2499 ASITSGGSTNYA 2571 CARGGPRFGGFRGYFDPW 10-37 2428 FTFTSYRMG 2500 AGISRFFGTAYY 2572 CARVTRWFGGLDVW A 10-38 2429 RTFSRYVMG 2501 ASISRFGRTNYA 2573 CARHHGLGILWWGTMDVW 10-39 2430 RTFSMG 2502 ASISRFGRTNYA 2574 CAKRSTWLPQHFDSW 10-40 2431 RTFSTYTMG 2503 ARIWRSGGNTY 2575 CARGVRGVFRAYFDHW YA 10-41 2432 RNLRMYRMG 2504 ALISRVGVTSYA 2576 CARGTSFFNFWSGSLGRVGF DSW 10-42 2433 ITIRTHAMG 2505 ATISRSGGNTYY 2577 CTTAGVLRYFDWFRRPYW A 10-43 2434 RTFRRYHMG 2506 AAITSGGRTNYA 2578 CTTDGLRYFDWFPWASAFDI W 10-44 2435 RTFRRYTMG 2507 AVISWSGGSTKY 2579 CARKGRWSGMNVW A 10-45 2436 RTFSWYPMG 2508 ASISWGGARTYY 2580 CARSTGPRGSGRYRAHWFDS A W 10-46 2437 RTFTSYRMG 2509 AAITWNSGRTRY 2581 CSPSSWPFYFGAW A 10-47 2438 RPLRRYVMG 2510 AAITNGGSTKYA 2582 CARGTPWRLLWFGTLGPPPA FDYW 10-48 2439 RTFRRYAMG 2511 AAINRSGSTEYA 2583 CARQHQDFWTGYYTVW 10-49 2440 RTFRRYTMG 2512 ASISRSGTTYYA 2584 CAKEGWRWLQLRGGFDYW 10-50 2441 RTLSTYNMG 2513 ASISRFGRTNYA 2585 CARRGKLSAAMHWFDPW 10-51 2442 RFFSTRVMG 2514 ARIWPGGSTYYA 2586 CARDRGIFGVSRW 10-52 2443 RFFSICSMG 2515 AGINWRSGGSTY 2587 CARGSGWWEYW YA 10-53 2444 RMFSSRSNMG 2516 ASISSGGTTAYA 2588 CARGFGRRFLEWLPRFDYW 10-54 2445 RTFSSARMG 2517 AGINMISSTKYA 2589 CAHFRRFLPRGYVDYW 10-55 2446 RTFRRYTMG 2518 ARIAGGSTYYA 2590 CARQQYYDFWSGYFRSGYFD LW 10-56 2447 HTFRNYGMG 2519 AAITSSGSTNYA 2591 CATVPPPRRFLEWLPRRLTYT W 10-57 2448 RTFSRYAMG 2520 ASITKFGSTNYA 2592 CAKERESRFLKWRKTDW 10-58 2449 RNLRMYRMG 2521 ASISRFGRTNYA 2593 CARHDSIGLFRHGMDVW 10-59 2450 RTFRRYAMG 2522 ARISSGGSTSYA 2594 CARDRGFGFWSGLRGYFDL W 10-60 2451 IPASMYLG 2523 AAITSGGRTSYA 2595 CAKRKKRGPLWFGGGGWGY W 10-61 2452 IPFRSRTFSAY 2524 AQITRGGSTNYA 2596 CARRHWFGFDYW AMG

TABLE 41 Membrane Protein VII Sequences SEQ ID Variant NO VH  9-1 2597 EVQLVESGGGLVQPGGSLRLSCAASGRTFSRLAMGWFRQAPGKEREFVAAISRSG RSTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARRSQILFTSRTDY EWGQGTLVTVSS  9-2 2598 EVQLVESGGGLVQPGGSLRLSCAASGSFSIAAMGWFRQAPGKEREFVATINYSGG GTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAVNTFDESAYAAF ACYDVVWGQGTLVTVSS  9-3 2599 EVQLVESGGGLVQPGGSLRLSCAASGRTFSRYAMGWFRQAPGKEREFVAAISRSG KSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAASSVFSDLRYRKN PKWGQGTLVTVSS  9-4 2600 EVQLVESGGGLVQPGGSLRLSCAASGRTFSKYAMGWFRQAPGKEREFVSHISRDG GRTFSSSTMGWFRQAPGKERELVALITPSSRTTYYADSVKGRFTISADNSKNTAYL QMNSLKPEDTAVYYCAIAGRGRWGQGTLVTVSS  9-5 2601 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYAMGWFRQAPGKEREFVASINWG GGNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKTKRTGIFTTAR MVDWGQGTLVTVSS  9-6 2602 EVQLVESGGGLVQPGGSLRLSCAASGRTFSRFAMGWFRQAPGKEREFVAAIRWSG GRTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAIEPGTIRNWRNRV PFARGNFGWGQGTLVTVSS  9-7 2603 EVQLVESGGGLVQPGGSLRLSCAASGLGIAFSRRTAMGWFRQAPGKEREFVAAIS WRGGNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARRWIPPGPI WGQGTLVTVSS  9-8 2604 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYPMGWFRQAPGKEREFVAAISRSG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKRLRSFASGGSY DWGQGTLVTVSS  9-9 2605 EVQLVESGGGLVQPGGSLRLSCAASGGTLRGYGMGWFRQAPGKEREFVASISRSG GSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARRRVTLFTSRAD YDWGQGTLVTVSS  9-10 2606 EVQLVESGGGLVQPGGSLRLSCAASGRMFSSRSMGWFRQAPGKEREFVALINRSG GSQFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAARRWIPPGPIWGQ GTLVTVSS  9-11 2607 EVQLVESGGGLVQPGGSLRLSCAASGRTFGRRAMGWFRQAPGKEREFVAGISRGG GTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAKGIWDYLGRRDF GDWGQGTLVTVSS 10-1 2608 EVQLVESGGGLVQPGGSLRLSCAASGLSSPPFDDFPMGWFRQAPGKEREFVSSIYS DDGDSMYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARQTFDFWSAS LGGNFWYFDLWGQGTLVTVSS 10-2 2609 EVQLVESGGGLVQPGGSLRLSCAASGGTFSSYSMGWFRQAPGKEREFVSAISWIIG SGGTTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTAGAGDSWGQG TLVTVSS 10-3 2610 EVQLVESGGGLVQPGGSLRLSCAASGSIFSTRTMGWFRQAPGKEREFVASITKFGS TNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTRGGGRFFDWLYLRW GQGTLVTVSS 10-4 2611 EVQLVESGGGLVQPGGSLRLSCAASGRTLWRSNMGWFRQAPGKEREFVASISSFG STKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGHGRYFDWLLFA RPPDYWGQGTLVTVSS 10-5 2612 EVQLVESGGGLVQPGGSLRLSCAASGRSLGIYRMGWFRQAPGKEREFVAAITSGG RKNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKRTIFGVGRWLDP WGQGTLVTVSS 10-6 2613 EVQLVESGGGLVQPGGSLRLSCAASGTTLTFRIMGWFRQAPGKEREFVPAISSTGL ASYTDSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCSKDRAPNCFACCPNGF DVWGQGTLVTVSS 10-7 2614 EVQLVESGGGLVQPGGSLRLSCAASGSRFSGRFNILNMGWFRQAPGKEREFVARI GYSGQSISYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGRFLGGTE WGQGTLVTVSS 10-8 2615 EVQLVESGGGLVQPGGSLRLSCAASGTLFKINAMGWFRQAPGKEREFVAQINRHG VTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGRTIFFGGGRYFD YWGQGTLVTVSS 10-9 2616 EVQLVESGGGLVQPGGSLRLSCAASGIPFRSRTMGWFRQAPGKEREFVAGITGSGR SQYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGARIFGSVAPWR GGNYYGMDVWGQGTLVTVSS 10-10 2617 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSFRMGWFRQAPGKEREFVAGISRGGS TNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARASGLWFRRPHVWG QGTLVTVSS 10-11 2618 EVQLVESGGGLVQPGGSLRLSCAASGRNFRRNSMGWFRQAPGKEREFVAGISWS GARTHYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVSRRPRSPPGY YYGMDVWGQGTLVTVSS 10-12 2619 EVQLVESGGGLVQPGGSLRLSCAASGRNLRMYRMGWFRQAPGKEREFVATIRWS DGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTRARLRYFDWLF PTNFDYWGQGTLVTVSS 10-13 2620 EVQLVESGGGLVQPGGSLRLSCAASGGLTFSSNTMGWFRQAPGKEREFVASISSSG RTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARRVRRLWFRSYFDL WGQGTLVTVSS 10-14 2621 EVQLVESGGGLVQPGGSLRLSCAASGFTLAYYAMGWFRQAPGKEREFVAAISWS GRNINYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARERARWFGKFS VSWGQGTLVTVSS 10-15 2622 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSFPMGWFRQAPGKEREFVAAISWSG STSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYSACGRLGFGAWGQGT LVTVSS 10-16 2623 EVQLVESGGGLVQPGGSLRLSCAASGISSSKRNMGWFRQAPGKEREFVATWTSRG ITTYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGGPPRLWGSYRRK YFDYWGQGTLVTVSS 10-17 2624 EVQLVESGGGLVQPGGSLRLSCAASGRTFSIYAMGWFRQAPGKEREFVARITRGGI TKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGLGWLLGYYWGQ GTLVTVSS 10-18 2625 EVQLVESGGGLVQPGGSLRLSCAASGRMYNSYSMGWFRQAPGKEREFVARISPG GTFYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTTSARSGWFWRYFD SWGQGTLVTVSS 10-19 2626 EVQLVESGGGLVQPGGSLRLSCAASGRTFRSYGMGWFRQAPGKEREFVASISRSG TTMYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARRGLLQWFGAPNS WFDPWGQGTLVTVSS 10-20 2627 EVQLVESGGGLVQPGGSLRLSCAASGRTIRTMGWFRQAPGKEREFVATINSRGITN YADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTTERDGLLWFRELFRPSW GQGTLVTVSS 10-21 2628 EVQLVESGGGLVQPGGSLRLSCAASGRSFSFNAMGWFRQAPGKEREFVARISRFG RTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKVHSYVWGGHSD YWGQGTLVTVSS 10-22 2629 EVQLVESGGGLVQPGGSLRLSCAASGRTYYAMGWFRQAPGKEREFVGAIDWSGR RITYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVRFSRLGGVIGRPI DSWGQGTLVTVSS 10-23 2630 EVQLVESGGGLVQPGGSLRLSCAASGRAFRRYTMGWFRQAPGKEREFVASITKFG STNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKDRGVLWFGELWY WGQGTLVTVSS 10-24 2631 EVQLVESGGGLVQPGGSLRLSCAASGRTFSNYRMGWFRQAPGKEREFVASINRGG STKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASGKGGSATIFHLSR RPLYFDYWGQGTLVTVSS 10-25 2632 EVQLVESGGGLVQPGGSLRLSCAASGITFSPYAMGWFRQAPGKEREFVATINWSG GYTVYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKRKNRGPLWFGG GGWGYWGQGTLVTVSS 10-26 2633 EVQLVESGGGLVQPGGSLRLSCAASGRTFSGFTMSSTWMGWFRQAPGKEREFVA GIITNGSTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARRVAYSSF WSGLRKHMDVWGQGTLVTVSS 10-27 2634 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYSMGWFRQAPGKEREFVASITPGG NTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCASRRRWLTPYIFWG QGTLVTVSS 10-28 2635 EVQLVESGGGLVQPGGSLRLSCAASGSIFSIGMGWFRQAPGKEREFVARIWWRSG ATYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAAISIFGRLKWGQGT LVTVSS 10-29 2636 EVQLVESGGGLVQPGGSLRLSCAASGRTFTSYRMGWFRQAPGKEREFVAEISSSG GYTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVGPLRFLAQRP RLRPDYWGQGTLVTVSS 10-30 2637 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSFRFRAMGWFRQAPGKEREFVALIFS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAREWGRWLQRGS YWGQGTLVTVSS 10-31 2638 EVQLVESGGGLVQPGGSLRLSCAASGRTFGSYGMGWFRQAPGKEREFVATISIGG VRTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGSGSGFMWYHG NNNYDRWRYWGQGTLVTVSS 10-32 2639 EVQLVESGGGLVQPGGSLRLSCAASGRTFRSYPMGWFRQAPGKEREFVASINRGG STNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGRYDFWSGYYR WFDPWGQGTLVTVSS 10-33 2640 EVQLVESGGGLVQPGGSLRLSCAASGRTFSRSDMGWFRQAPGKEREFVAAISWSG GSTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATVPPPRRFLEWLP RRLTYIWGQGTLVTVSS 10-34 2641 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYTMGWFRQAPGKEREFVASMRGS RSYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARMSGFPFLDYWGQ GTLVTVSS 10-35 2642 EVQLVESGGGLVQPGGSLRLSCAASGSIFRLSTMGWFRQAPGKEREFVASISSFGST YYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARTRGIFLWFGESFDY WGQGTLVTVSS 10-36 2643 EVQLVESGGGLVQPGGSLRLSCAASGIAFRIRTMGWFRQAPGKEREFVASITSGGS TNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGGP RFGGFRGYFDP WGQGTLVTVSS 10-37 2644 EVQLVESGGGLVQPGGSLRLSCAASGFTFTSYRMGWFRQAPGKEREFVAGISRFF GTAYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARVTRWF GGLDV WGQGTLVTVSS 10-38 2645 EVQLVESGGGLVQPGGSLRLSCAASGRTFSRYVMGWFRQAPGKEREFVASISRFG RTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARHHGLGILWWGT MDVWGQGTLVTVSS 10-39 2646 EVQLVESGGGLVQPGGSLRLSCAASGRTFSMGWFRQAPGKEREFVASISRFGRTN YADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKRSTWLPQHFDSWGQG TLVTVSS 10-40 2647 EVQLVESGGGLVQPGGSLRLSCAASGRTFSTYTMGWFRQAPGKEREFVARIWRSG GNTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGVRGVFRAYFD HWGQGTLVTVSS 10-41 2648 EVQLVESGGGLVQPGGSLRLSCAASGRNLRMYRMGWFRQAPGKEREFVALISRV GVTSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGTSFFNFWSGSL GRVGFDSWGQGTLVTVSS 10-42 2649 EVQLVESGGGLVQPGGSLRLSCAASGITIRTHAMGWFRQAPGKEREFVATISRSGG NTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCTTAGVLRYFDWFRR PYWGQGTLVTVSS 10-43 2650 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYHMGWFRQAPGKEREFVAAITSGG RTNYADSVKGRFTISADNSKNTAYLQMNSLKP EDTAVYYCTTD GLRYFDWFPWA SAFDIWGQGTLVTVSS 10-44 2651 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYTMGWFRQAPGKEREFVAVISWSG GSTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARKGRWSGMNVW GQGTLVTVSS 10-45 2652 EVQLVESGGGLVQPGGSLRLSCAASGRTFSWYPMGWFRQAPGKEREFVASISWG GARTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARSTGPRGSGRY RAHWFDSWGQGTLVTVSS 10-46 2653 EVQLVESGGGLVQPGGSLRLSCAASGRTFTSYRMGWFRQAPGKEREFVAAITWNS GRTRYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCSPSSWPFYFGAWG QGTLVTVSS 10-47 2654 EVQLVESGGGLVQPGGSLRLSCAASGRPLRRYVMGWFRQAPGKEREFVAAITNG GSTKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGTPWRLLWFGT LGPPPAFDYWGQGTLVTVSS 10-48 2655 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYAMGWFRQAPGKEREFVAAINRSG STEYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARQHQDFWTGYYTV WGQGTLVTVSS 10-49 2656 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYTMGWFRQAPGKEREFVASISRSG TTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKE GWRWLQLRGGF DYWGQGTLVTVSS 10-50 2657 EVQLVESGGGLVQPGGSLRLSCAASGRTLSTYNMGWFRQAPGKEREFVASISRFG RTNYADSVKGRFTISADNSKNTAYLQMNSLKP EDTAVYYCARRGKLSAAMHWF DPWGQGTLVTVSS 10-51 2658 EVQLVESGGGLVQPGGSLRLSCAASGRFFSTRVMGWFRQAPGKEREFVARIWPGG STYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDRGIFGVSRWGQ GTLVTVSS 10-52 2659 EVQLVESGGGLVQPGGSLRLSCAASGRFFSICSMGWFRQAPGKEREFVAGINWRS GGSTYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGSGWWEYWG QGTLVTVSS 10-53 2660 EVQLVESGGGLVQPGGSLRLSCAASGRMFSSRSNMGWFRQAPGKEREFVASISSG GTTAYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARGFGRRFLEWLP RFDYWGQGTLVTVSS 10-54 2661 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSARMGWFRQAPGKEREFVAGINMIS STKYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAHFRRFLPRGYVDY WGQGTLVTVSS 10-55 2662 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYTMGWFRQAPGKEREFVARIAGGS TYYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARQQYYDFWSGYFRS GYFDLWGQGTLVTVSS 10-56 2663 EVQLVESGGGLVQPGGSLRLSCAASGHTFRNYGMGWFRQAPGKEREFVAAITSSG STNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCATVPPPRRFLEWLPR RLTYTWGQGTLVTVSS 10-57 2664 EVQLVESGGGLVQPGGSLRLSCAASGRTFSRYAMGWFRQAPGKEREFVASITKFG STNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKERESRFLKWRKT DWGQGTLVTVSS 10-58 2665 EVQLVESGGGLVQPGGSLRLSCAASGRNLRMYRMGWFRQAPGKEREFVASISRFG RTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARHDSIGLFRHGMD VWGQGTLVTVSS 10-59 2666 EVQLVESGGGLVQPGGSLRLSCAASGRTFRRYAMGWFRQAPGKEREFVARISSGG STSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARDRGFGFWSGLRG YFDLWGQGTLVTVSS 10-60 2667 EVQLVESGGGLVQPGGSLRLSCAASGIPASMYLGWFRQAPGKEREFVAAITSGGR TSYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCAKRKKRGPLWFGGGG WGYWGQGTLVTVSS 10-61 2668 EVQLVESGGGLVQPGGSLRLSCAASGIPFRSRTFSAYAMGWFRQAPGKEREFVAQI TRGGSTNYADSVKGRFTISADNSKNTAYLQMNSLKPEDTAVYYCARRHWFGFDY WGQGTLVTVSS

While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. 

1. An antibody or antibody fragment comprising a variable domain, heavy chain region (VH) and a variable domain, light chain region (VL), wherein VH comprises complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein VL comprises complementarity determining regions CDRL1, CDRL2, and CDRL3, and wherein (a) an amino acid sequence of CDRH1 is as set forth in any one of SEQ ID NOs: 151-165, 241-255, 331-357, and 547-575; (b) an amino acid sequence of CDRH2 is as set forth in any one of SEQ ID NOs: 166-180, 256-270, 358-384, and 576-604; (c) an amino acid sequence of CDRH3 is as set forth in any one of SEQ ID NOs: 181-195, 271-285, 385-411, and 605-633; (d) an amino acid sequence of CDRL1 is as set forth in any one of SEQ ID NOs: 196-210, 286-300, 412-438, and 634-662; (e) an amino acid sequence of CDRL2 is as set forth in any one of SEQ ID NOs: 211-225, 301-315, 439-465, and 663-691; and (f) an amino acid sequence of CDRL3 is as set forth in any one of SEQ ID NOs: 226-240, 316-330, 466-492, and 692-720.
 2. The antibody or antibody fragment of claim 1, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 155; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 170; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 185; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 200; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 215; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO:
 230. 3. The antibody or antibody fragment of claim 1, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 152; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 167; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 182; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 197; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 212; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO:
 227. 4. The antibody or antibody fragment of claim 1, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 335; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 362; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 389; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 199; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 214; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO:
 229. 5. The antibody or antibody fragment of claim 1, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 336; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 363; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 390; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 201; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 216; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO:
 231. 6. The antibody or antibody fragment of claim 1, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 158; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 173; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 188; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 203; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 218; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO:
 233. 7. The antibody or antibody fragment of claim 1, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 551; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 580; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 609; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 290; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 305; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO:
 320. 8. The antibody or antibody fragment of claim 1, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 549; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 578; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 607; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 292; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 307; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO:
 322. 9. The antibody or antibody fragment of claim 1, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 552; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 581; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 610; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 291; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 306; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO:
 321. 10. The antibody or antibody fragment of claim 1, wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 554; (b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 583; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 612; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 288; (e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO: 303; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ ID NO:
 318. 11. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment binds to a spike glycoprotein or a receptor binding domain of the spike glycoprotein.
 12. (canceled)
 13. (canceled)
 14. (canceled)
 15. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment comprises a K_(D) of less than 10 nM.
 16. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment comprises a K_(D) of less than 5 nM.
 17. An antibody or antibody fragment comprising a variable domain, heavy chain region (VH) wherein VH comprises complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein (a) an amino acid sequence of CDRH1 is as set forth in any one of SEQ ID NOs: 1-50, 779-919, 1344-1523, and 2381-2452; (b) an amino acid sequence of CDRH2 is as set forth in any one of SEQ ID NOs: 51-100, 920-1061, 1524-1703, and 2453-2524; and (c) an amino acid sequence of CDRH3 is as set forth in any one of SEQ ID NOs: 101-150, 1062-1202, 1704-1883, and 2525-2596.
 18. The antibody or antibody fragment of claim 17, wherein (a) the amino acid sequence of CDRH1 is as set forth in any one of SEQ ID NOs: 1414, 1447, 1474, 1344, 1363, 1487, 780, 782, 39, 832, 869, 889, and 908; (b) the amino acid sequence of CDRH2 is as set forth in any one of SEQ ID NOs: 1594, 1627, 1654, 1524, 1543, 1667, 921, 923, 89, 973, 1010, 1030, and 1049; and (c) the amino acid sequence of CDRH3 is as set forth in any one of SEQ ID NOs: 1774, 1807, 1834, 1704, 1723, 1847, 1063, 1065, 139, 1115, 1152, 1172, and
 1191. 19.-30. (canceled)
 31. An antibody or antibody fragment comprising a variable domain, heavy chain region (VH) and a variable domain, light chain region (VL), wherein the VH comprises an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 493-519 and 721-749, and wherein the VL comprises an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 520-546 and 750-778.
 32. An antibody or antibody fragment comprising a variable domain, heavy chain region (VH) comprising an amino acid sequence at least about 90% identical to a sequence as set forth in any one of SEQ ID NOs: 1884-2063, 2302-2380, and 2597-2668.
 33. The antibody or antibody fragment of claim 32, wherein the VH comprises an amino acid sequence at least about 90% identical to SEQ ID NO:
 1954. 34. The antibody or antibody fragment of claim 32, wherein the VH comprises an amino acid sequence at least about 90% identical to SEQ ID NO:
 1987. 35. The antibody or antibody fragment of claim 32, wherein the VH comprises an amino acid sequence at least about 90% identical to SEQ ID NO:
 2014. 36.-64. (canceled) 